Substituted 4-phenyltetrahydroisoquinolinium, process for their preparation, their use as a medicament, and medicament containing them

ABSTRACT

The invention relates to compounds of the formula I  
                 
in which R1 to R9 are as defined herein. In one embodiment, these compounds may be used as antihypertensives, for reducing or preventing ischemia-induced damage, as medicaments for surgical intervention for the treatment of ischemias of the nervous system, of stroke and of cerebral edema, of shock, of impaired respiratory drive, for the treatment of snoring, as laxative, as agent against ectoparasites, to prevent the formation of gallstones, as antiatherosclerotics, agents against late complications of diabetes, cancers, fibrotic disorders, endothelial dysfunction, organ hypertrophies and hyperplasias. In one embodiment, the compounds may be inhibitors of the cellular sodium-proton antiporter and influence serum lipoproteins and thus be used for the prophylaxis and for the regression of atherosclerotic lesions.

This application claims the benefit of foreign priority under 35 U.S.C.§119 of German patent application no. 10159714.2 , filed on Dec. 5, 2001and the contents of which are incorporated by reference herein.

The invention relates to compounds of the formula I

wherein:

-   -   R1, R2, R3 and R4 are independently of one another H, F, Cl, Br,        I, CN, NO₂, OH, NH₂, C_(a)H_(2a+1), C_(qq)H_(2qq−1),        OC_(b)H_(2b+1), COOR10, OCOR10, COR10 or O_(x)-(CH₂)_(y)-phenyl;        wherein        -   a and b are independently of one another 1, 2, 3, 4, 5, 6, 7            or 8, wherein the groups C_(a)H_(2a+1) and OC_(b)H_(2b+1)            independently of one another are unsubstituted or            substituted where one or more H atoms are replaced by F            atoms;        -   qq is 3, 4, 5, 6, 7 or 8, wherein the group C_(qq)H2qq−1 is            unsubstituted or substituted where one or more H atoms are            replaced by F atoms;        -   R10 is H or C_(c)H_(2c+1);            -   c is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group CcH2c+1                is unsubstituted or substituted where one or more H                atoms are replaced by F atoms;        -   x is zero or 1;        -   y is zero, 1, 2, 3 or 4; where the phenyl ring in the group            O_(x)—(CH₂)_(y)-phenyl is unsubstituted or substituted by            1-3 independently chosen from F, Cl, Br, CN, NO₂, OH, NH₂            and C_(d)H_(2d+1),            -   d is 1, 2, 3 or 4, wherein the group C_(d)H_(2d+1) is                unsubstituted or substituted where one or more H atoms                are replaced by F atoms;    -   or    -   R1, R2, R3 and R4 are independently of one another chosen from a        heteroaryl with at least one heteroatom chosen from 1, 2, 3 or 4        N atoms, 1 oxygen atom and 1 S atom, present as ring atoms;    -   or    -   R1, R2, R3 and R4 are independently of one another CONR11R12 or        NR11R12;    -   wherein        -   R11 and R12 are independently of one another H,            C_(e)H_(2e+1), C_(rr)H_(2rr−1);            -   e is 1, 2, 3, 4, 5, 6, 7 or 8;            -   rr is 3, 4, 5, 6, 7, or 8, wherein the groups                C_(e)H_(2e+1) and C_(rr)H_(2rr−1) independently of one                another are unsubstituted or substituted where one or                more H atoms are replaced by F atoms and/or one or more                CH₂ groups are replaced by O or NR13;                -   R13 is H or C_(f)H_(2f+1);                -    f is 1, 2, 3 or 4, wherein the group C_(f)H_(2f+1)                    is unsubsitituted or substituted where one or more H                    atoms are replaced by F atoms;                -   or                -   R13 and a CH₂ group of R11 or R12 together with the                    N atom to which they are bonded form a 5- or                    6-membered ring;        -   or        -   R11 and R12 together with the N atom to which they are            bonded form a 5-, 6- or 7-membered ring;        -   or        -   R11 and R12 are independently of one another COR14, CSR14 or            SO₂R14;        -   wherein            -   R14 is C_(g)H_(2g+1);                -   g is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group                    C_(g)H_(2g+1) is unsubsitituted or substituted where                    one or more H atoms are replaced by F atoms, and/or                    one or more CH₂ groups are replaced by O or NR13;    -   or    -   R1, R2, R3 and R4 are independently of one another        —O_(h)—SO_(j)—R15, with        -   h is zero or 1;        -   j is zero, 1 or 2;        -   R15 is C_(k)H_(2k+1), OH, OC_(l)H_(2l+1) or NR17R18;            -   k is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group                C_(k)H_(2k+1) is unsubsitituted or substituted where one                or more H atoms are replaced by F atoms;            -   l is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group                OC_(l)H_(2l+1) is unsubsitituted or substituted where                one or more H atoms are replaced by F atoms;            -   R17 and R18 are independently of one another H or                C_(m)H_(2m+1);                -   m is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group                    C_(m)H_(2m+1) is unsubstituted or substituted where                    one or more H atoms is replaced by F atoms and/or                    one or more CH₂ groups are replaced by O, CO, CS or                    NR19;                -    R19 is H or C_(n)H_(2n+1);                -    n is 1, 2, 3 or 4, wherein the group C_(n)H_(2n+1)                    is unsubstituted or substituted where one or more H                    atoms are replaced by F atoms;                -    or                -    R19 and a CH₂ group of R17 or R18 together with the                    N atom to which they are bonded form a 5- or                    6-membered ring;            -   or            -   R17 and R18 together with the N atom to which they are                bonded form a 5-, 6- or 7-membered ring;    -   but where R2 does not equal H in any of the foregoing        definitions,    -   R5 is H, C_(p)H_(2p+1), C_(ss)H_(2ss−1), COR20 or SO₂R20;        wherein        -   p is 1, 2, 3, 4, 5, 6, 7 or 8,        -   ss is 3, 4, 5, 6, 7 or 8,        -   R20 is C_(q)H_(2q+1);            -   q is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the groups                C_(p)H_(2p+1), C_(ss)H_(2ss−1) and C_(q)H_(2q+1)                independently of one another are unsubstituted or                substituted where one or more H atoms are replaced by F                atoms and/or one or more CH₂ groups are replaced by O or                NR21;            -   R21 is H or C_(r)H_(2r+1);                -   r is 1, 2, 3 or 4; wherein the group C_(r)H_(2r+1)                    is unsubstituted or substituted where one or more H                    atoms are replaced by F atoms;    -   R6 is H, F, Cl, Br, I, C_(s)H_(2s+1), C_(dd)H_(2dd−1), OH,        OC_(t)H_(2t+1) or OCOR22; wherein        -   s and t are independently of one another 1, 2, 3, 4, 5, 6, 7            or 8;        -   dd is 3, 4, 5, 6, 7 or 8, wherein the groups C_(s)H_(2s+1),            C_(dd)H_(2dd−)1 and OC_(t)H_(2t+1) independently of one            another are unsubstituted or substituted where one or more H            atoms are replaced by F atoms;        -   R22 is C_(u)H_(2u+1);        -   u 1, 2, 3 or 4, wherein the group C_(u)H_(2u+1) is            unsubstituted or substituted where one or more H atoms are            replaced by F atoms;    -   R7, R8 and R9 are independently of one another        —O_(v)—SO_(w)—R23; wherein        -   v is zero or 1;        -   w is zero, 1 or 2;        -   R23 is C_(nn)H_(2nn+1), C_(mm)H_(2mm−1), OH,            OC_(pp)H_(2pp+1) or NR25R26;            -   nn and pp are independently of one another 1, 2, 3, 4,                5, 6, 7 or 8, mm is 3, 4, 5, 6, 7 or 8, wherein the                groups C_(nn)H_(2nn+1), C_(mm)H_(2mm−1) and                OC_(pp)H_(2pp+1) independently of one another are                unsubstituted or substituted where one or more H atoms                are replaced by F atoms;            -   R25 and R26 are independently of one another H, CN,                C_(z)H_(2z+1), or C_(zz)H_(2zz−1);                -   z is 1, 2, 3, 4, 5, 6, 7 or 8;                -   zz is 3, 4, 5, 6, 7 or 8, wherein the group                    C_(z)H_(2z+1) is unsubstituted or substituted where                    one or more H atoms are replaced by F atoms and,                    wherein the group C_(z)H_(2z+1), is unsubstituted or                    substituted where one or more H atoms are replaced                    by F atoms and/or one or more CH₂ groups are                    replaced by O, CO, CS or NR27;                -   R27 is H or C_(aa)H_(2aa+1);                -    aa is 1, 2, 3 or 4, wherein the group                    C_(aa)H_(2aa+1) is unsubstituted or substituted                    where one or more H atoms are replaced by F atoms;                -   or                -   R27 and a CH₂ group of R25 or R26 together with the                    N atom to which they are bonded form a 5- or                    6-membered ring;                -   or                -   R25 and R26 together with the N atom to which they                    are bonded form a 5-, 6- or 7-membered ring;    -   or    -   R7, R8 and R9 are independently of one another NR32COR30,        NR32CSR30 or NR32SO_(bb)R30;        -   R30 is H, C_(cc)H_(2cc+1), C_(yy)H_(2yy−1), pyrrolidinyl or            piperidinyl, wherein the pyrrolidinyl or piperidinyl is            unsubstituted or substituted where a CH₂ group is replaced            by O or NR33;        -   R32 and R33 are independently of one another H or            C_(h)H_(2h+1);        -   bb is 2 or 3;        -   cc is 1, 2, 3, 4, 5, 6, 7 or 8;        -   yy is 3, 4, 5, 6, 7 or 8;        -   h is 1, 2, 3, 4, 5, 6, 7 or 8,        -   wherein the group C_(h)H_(2h+1) is unsubstituted or            substituted where one or more H atoms are replaced by F            atoms, and        -   whrein the groups C_(cc)H_(2cc+1) and C_(yy)H_(2yy−1)            independently of one another are unsubstituted or            substituted where one or more H atoms are replaced by F            atoms and/or one or more CH₂ groups are replaced by NR31            and/or one CH₂ group are replaced by O;        -   R31 is H, C_(kk)H_(2kk+1), COR65 or SO₂ R65;            -   kk is 1, 2, 3, or 4; wherein the group C_(kk)H_(2kk+1)                is unsubstituted or substituted where one or more H                atoms are replaced by F atoms,            -   R65 is H, or C_(xx)H_(2xx+1);                -   xx is 1, 2, 3 or 4, wherein the group                    C_(xx)H_(2xx+1) is unsubstituted or substituted                    where one or more H atoms are replaced by F atoms;        -   or        -   R31 together with a CH₂ group of R30 forms a 5-, 6- or            7-membered ring;        -   or        -   R30 is a 5- or 6-membered heteroaryl with at least one            hetero atom chosen from 1, 2, 3 or 4 N atoms, zero, 1 S atom            and 1 O atom,            -   which is unsubstituted or substituted by up to three                substituents chosen from F, Cl, Br, I, C_(oo)H_(2oo+1),                and            -   NR70R71;            -   R70 and R71 are independently of one another H,                C_(uu)H_(2uu+1) or COR72;                -   R72 is H, or C_(vv)H_(2vv+1);                -   oo, uu and vv are independently of one another 1, 2,                    3, 4, 5, 6, 7 or 8, wherein the groups                    C_(oo)H_(2oo+1), C_(uu)H_(2uu+1) and C_(vv)H_(2vv+1)                    independently of one another are unsubstituted or                    substituted where one or more H atoms are replaced                    by F atoms;    -   or    -   R7, R8 and R9 are independently of one another H, F, Cl, Br, I,        NO₂, CN, OH, NH₂, C_(ee)H_(2ee+1), C_(ww)H_(2ww−1),        OC_(ff)H_(2ff+1), NR40R41, CONR40R41, COOR42, COR42 or OCOR42,        -   ee and ff are independently of one another 1, 2, 3, 4, 5, 6,            7 or 8;        -   ww is 3, 4, 5, 6, 7 or 8, wherein the groups            C_(ee)H_(2ee+1), C_(ww)H_(2ww−1) and OC_(ff)H_(2ff+1)            independently of one another are unsubstituted or            substituted where one or more H atoms are replaced by F            atoms;        -   R40 and R41 are independently of one another H,            C_(tt)H_(2tt+1) or C(NH)NH₂;            -   tt is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group                C_(tt)H_(2tt+1) is unsubstituted or substituted where                one or more H atoms are replaced by F atoms and/or where                one or more CH₂ groups are replaced by O or NR44;            -   R44 is H or C_(gg)H_(2gg+1);                -   gg is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group                    C_(gg)H_(2gg+1) is unnsubstituted or substituted                    where one or more H atoms are replaced by F atoms            -   or            -   R44 forms a 5- or 6-membered ring together with a (CH₂)                group of R40 or R41 and the N atom to which they are                bound;        -   or        -   R40 and R41 with the N atom to which they are bonded form a            5- or 6-membered ring;        -   R42 is H or C_(hh)H_(2hh+1);            -   hh is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group                C_(hh)H_(2hh+1) is unnsubstituted or substituted where                one or more H atoms are replaced by F atoms;    -   with the proviso that two substituents chosen from the group R7,        R8 and R9 can not simultaneously be OH and OCH₃,    -   and that at least one of the substituents R7, R8 and R9 is        chosen from CONR4OR41, —O_(v)—SO_(w)—R23, NR32COR30, NR32CSR30        and NR32SO_(bb)R30;    -   and the pharmaceutically acceptable salts and trifluoroacetates        thereof.

In another embodiment, compounds of the formula I are chosen from:

-   -   R1, R2, R3 and R4 are independently of one another, H, F, Cl,        Br, I, CN, NO₂, OH, NH₂, C_(a)H_(2a+1), cycloalkyl with 3, 4, 5        or 6 C atoms, OC_(b)H_(2b+1), or COOR10;    -   wherein        -   a and b are independently of one another 1, 2, 3 or 4,            wherein the group C_(a)H_(2a+1) is unsubstituted or            substituted where one or more H atoms are replaced by F            atoms;        -   R10 is H or C_(c)H_(2c+1);        -   c is 1, 2, 3 or 4, wherein the group C_(c)H_(2c+1) is            unsubstituted or substituted where one or more H atoms are            replaced by F atoms;        -   or    -   R1, R2, R3 and R4 are independently of one another a 5- or        6-membered heteroaryl choawn from pyridyl, imidazolyl,        pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl and        oxazolyl;    -   or    -   R1, R2, R3 and R4 are independently of one another CONR11 R12 or        NR11 R12;    -   wherein        -   R11 and R12 are independently of one another H,            C_(e)H_(2e+1), C_(rr)H_(2rr−1);            -   e is 1, 2, 3 or 4,            -   rr is 3, 4, 5 or 6, wherein the groups C_(e)H_(2e+1) and                C_(rr)H_(2rr−1) independently of one another are                unsubstituted or substituted where one or more H atoms                are replaced by F atoms;        -   or        -   R11 and R12 independently of one another are hydroxyethyl,            N,N-dimethylaminoethyl, N,N-diethylaminoethyl,            pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl,            morpholinoethyl or piperidinoethyl;        -   or        -   R11 and R12 together with the N atom to which they are            bonded form a pyrrolidine, piperidine, N-methylpiperazine,            piperazine or morpholine ring;        -   or        -   R11 and R12 are independently of one another COR14, CSR14,            CONHR14, CSNHR14 or SO₂R14; wherein            -   R14 is C_(g)H_(2g+1);                -   g is 1, 2, 3 or 4, wherein the group C_(g)H_(2g+1)                    is unsbustituted or substituted where one or more H                    atoms are replaced by F atoms;    -   or    -   R1, R2, R3 and R4 are independently of one another OSO₃H, SO₃H,        SO₂R₁₅;    -   wherein        -   R15 is C_(k)H_(2k+1), OC_(l)H_(2l+1) or NR17R18;            -   k is 1, 2, 3 or 4, wherein the group C_(k)H_(2k+1) is                unsubstituted or substituted where one ore more H atoms                are replaced by F atoms;            -   l is 1, 2, 3 or 4, wherein the group OC_(l)H_(2l+1) is                unsubstituted or substituted where one ore more H atoms                are replaced by F atoms;            -   R17 and R18 are independently of one another H, or                C_(m)H_(2m+1), in which the first CH₂ group bonded to                the nitrogen of NR17R18 is replaced by CO and the second                CH₂ group is replaced by NR19;                -   m 1, 2, 3, 4 or 5, wherein the group C_(m)H_(2m+1)                    is unsubstituted or substituted where one or more H                    atoms is replaced by F atoms;                -   R19 is H or C_(n)H_(2n+1);                -    n is 1, 2, 3 or 4, wherein the group C_(n)H_(2n+1)                    is unsubstituted or substituted where one or more H                    atoms is replaced by F atoms;            -   or            -   R17 and R18 together with the N atom to which they are                bonded form a 5- or 6-membered ring;    -   but where R2 does not equal H in any of the foregoing        definitions,    -   R5 is H, or C_(p)H_(2p+1);        -   p is 1, 2, 3 or 4, wherein the group C_(p)H_(2p+1) is            unsubstituted or substituted where one or more H atoms is            replaced by F atoms;    -   R6 is H, C_(s)H_(2s+1), OC_(t)H_(2t+1) or OCOR22;        -   s and t are independently of one another 1, 2, 3 or 4,            wherein the groups C_(s)H_(2s+1) and OC_(t)H_(2t+1)            independently of another are unsubstituted or substituted            where one or more H atoms is replaced by F atoms;        -   R22 is C_(u)H_(2u+1);            -   u is 1, 2, 3 or 4; wherein the group C_(u)H_(2u+1) is                unsubstituted or substituted where one or more H atoms                is replaced by F atoms;    -   R7, R8 and R9 are independently of one another OSO₃H, SO₃H or        SO₂R23;    -   wherein        -   R23 is C_(nn)H_(2nn+1), C_(mm)H_(2mm−1), OC_(pp)H_(2pp+1) or            NR25R26;            -   nn and pp are independently of one another 1, 2, 3, 4 or                5,        -   mm is 3, 4, 5 or 6, wherein the groups C_(nn)H_(2nn+1),            C_(mm)H_(2mm−1) and OC_(pp)H_(2pp+1) independently of            another are unsubstituted or substituted where one or more H            atoms is replaced by F atoms;        -   R25 and R26 are independently of one another H, CN, or            C_(z)H_(2z+1), in which a first CH₂ group bonded to the            nitrogen of NR25R26 is replaced by CO or CS and a second CH₂            is replaced by NR27;            -   z is 1, 2, 3, 4, 5 or 6; wherein the group C_(z)H_(2z+1)                is unsubstituted or substituted where one or more H                atoms are replaced by F atoms;            -   R27 is H or C_(aa)H_(2aa+1);                -   aa is 1, 2, 3 or 4, wherein the group                    C_(aa)H_(2aa+1) is unsubstituted or substituted                    where one or more H atoms are replaced by F atoms;            -   or            -   R27 and a CH₂ group of R25 or R26 together with the N                atom to which they are bonded form a 5- or 6-membered                ring;        -   or        -   R25 and R26 together with the N atom to which they are            bonded form a 5- or 6-membered ring;    -   or    -   R7, R8 and R9 are independently of one another NR32COR30,        NR32CSR30 or NR32SO₂R30; wherein        -   R30 is H, OH, C_(cc)H_(2cc+1), C_(yy)H_(2yy−1), pyrrolidinyl            or piperidinyl, wherein the pyrrolidinyl or piperidinyl is            unsubstituted or substituted where a CH₂ group is replaced            by O or NR33;        -   R32 and R33 are independently of one another H or            C_(h)H_(2h+1);            -   cc is 1, 2, 3, 4, 5, 6, 7 or 8;            -   yy is 3, 4, 5 or 6;        -   h is 1, 2, 3 or 4; wherein the group C_(h)H_(2h+1) is            unsubstituted or substituted where one or more H atoms are            replaced by F atoms, and wherein the groups C_(cc)H_(2cc+1)            and C_(yy)H_(2yy−1) independently of one another are            unsubstituted or substituted where one or more H atoms are            replaced by F atoms and/or one or more CH₂ groups to be            replaced by NR31 and/or one CH₂ group to be replaced by O;        -   R31 is H, C_(kk)H_(2kk+1), COR65 or SO₂ R65;            -   kk is 1, 2, 3, or 4, wherein the group C_(kk)H_(2kk+1)                is unsubstituted or substituted where one or more H                atoms are replaced by F atoms,            -   R65 is H, or C_(xx)H_(2xx+1);                -   xx is 1, 2, 3 or 4, wherein the group                    C_(xx)H_(2xx+)1 is unsubstituted where one or more H                    atoms are replaced by F atoms;        -   or        -   R31 together with a CH₂ group of R30 and the N atom to which            they are jointly bonded form form a 5- or 6-membered ring;        -   or        -   R30 is a 5- or 6-membered heteroaryl chosen from pyridyl,            imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl,            thienyl, thiazolyl and oxazolyl, which is unsubstituted or            substituted by up to three substituents chosen from F, Cl,            Br, I, C_(oo)H_(2oo+1), and NR7OR71,            -   R70 and R71 are independently of one another H,                C_(uu)H_(2uu+1) or COR72;                -   R72 is H, or C_(vv)H_(2vv+1);            -   oo, uu and w are independently of one another 1, 2, 3 or                4, wherein the groups C_(oo)H_(2oo+1), C_(uu)H_(2uu+1)                and C_(vv)H_(2vv+1) independently of one another are                unsubstituted or substituted where one or more H atoms                are replaced by F atoms;    -   or    -   R7, R8 and R9 are independently of one another H, F, Cl, Br, I,        NO₂, CN, OH, NH₂, C_(ee)H_(2ee+1), C_(ww)H_(2ww−1),        OC_(ff)H_(2ff+1), NR40R41, CONR40R41, COOR42, COR42 or OCOR42;        -   ee and ff are independently of one another 1, 2, 3 or 4;        -   ww is 3, 4, 5 or 6, wherein the groups C_(ee)H_(2ee+1),            C_(ww)H_(2ww−1) and OC_(ff)H_(2ff+1) independently of one            another are unsubstituted or substituted where one or more H            atoms are replaced by F atoms;        -   R40 and R41 are independently of one another H,            C_(tt)H_(2tt+1), or C(NH)NH₂;            -   tt is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group                C_(tt)H_(2tt+1) is unsubstituted or substituted where                one or more H atoms are replaced by F atoms;        -   or        -   R40 and R41 are independently of one another chosen from            hydroxyethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl,            pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl,            morpholinoethyl and piperidinoethyl;        -   or        -   R40 and R41 together with the N atom to which they are            bonded form a ring chosen from pyrrolidine, piperidine,            N-methylpiperazine, piperazine and morpholine;        -   R42 is H or C_(hh)H_(2hh+1);            -   hh is 1, 2, 3 or 4, wherein the group C_(hh)H_(2hh+1) is                unsubstituted or substituted where one or more H atoms                are replaced by F atoms;    -   with the proviso that two substituents chosen from the group R7,        R8 and R9 can not simultaneously be OH and OCH₃,    -   and that at least one of the substituents R7, R8 and R9 is        chosen from CONR4OR41, —O_(v)—SO_(w)—R²³, NR32COR30, NR32CSR30        and NR32SO_(bb)R30;    -   and the pharmaceutically acceptable salts and trifluoroacetates        thereof.

In another embodiment, compounds of the formula I are chosen from:

-   -   R1, R2, R3 and R4 are independently of one another H, F, Cl, Br,        OH, NH₂,    -   C_(a)H_(2a+1), cycloalkyl with 3, 4, 5 or 6 C atoms, or        OC_(b)H_(2b+1); wherein        -   a and b are independently of one another 1, 2, 3 or 4,            wherein the groups C_(a)H_(2a+1) and OC_(b)H_(2b+1)            independenly of one another are unsubstituted or substituted            where one or more H atoms are replaced by F atoms;    -   or    -   R1, R2, R3 and R4 are independently of one another NR11 R12;        -   R11 and R12 are independently of one another H,            C_(e)H_(2e+1), or C_(rr)H_(2rr−1);            -   e is 1, 2, 3 or 4,            -   rr is 3, 4, 5 or 6, wherein the groups C_(e)H_(2e+1) and                C_(rr)H_(2rr−1) independenly of one another are                unsubtituted or substituted where one or more H atoms                are replaced by F atoms;        -   or        -   R11 and R12 together with the N atom to which they are            bonded form a ring chosen from pyrrolidine, piperidine,            N-methylpiperazine, piperazine and morpholine;        -   or        -   R11 and R12 are independently of one another COR14, CSR14,            CONHR14, CSNHR14 or SO₂R14; wherein            -   R14 is C_(g)H_(2g+1);                -   g is 1, 2, 3 or 4, wherein the group C_(g)H_(2g+1)                    is unsubstituted or substituted where one or more H                    atoms are replaced by F atoms;    -   or    -   R1, R2, R3 and R4 are independently of one another OSO₃H, SO₃H,        or SO₂R15;        -   R15 is C_(k)H_(2k+1) or NR17R18;            -   k is 1, 2, 3 or 4, wherein the group C_(k)H_(2k+1) is                unsubstituted or substituted where one or more H atoms                are replaced by F atoms;            -   R17 and R18 are independently of one another H or                C_(m)H_(2m+1);                -   m is 1, 2, 3, 4 or 5, wherein the group                    C_(m)H_(2m+1) is unsubstituted or substituted where                    one ore more H atoms are replaced by F atoms;            -   or            -   R17 and R18 together with the N atom to which they are                bonded form a 5- or 6-membered ring;    -   but where R2 does not equal H in any of the foregoing        definitions;    -   R5 is methyl or trifluoromethyl;    -   R6 is H;    -   R7, R8 and R9 are independently of one another OSO₃H, SO₃H or        SO₂R23;    -   wherein        -   R23 is C_(nn)H_(2nn+1) or NR25R26;        -   nn is 1, 2, 3, 4 or 5, wherein the group C_(nn)H_(2nn+1) is            unsubstituted or substituted where one ore more H atoms are            replaced by F atoms;        -   R25 and R26 are independently of one another H, CN or            C_(z)H_(2z+1) in which a first CH₂ group bonded to the            nitrogen of NR25R26 is replaced by CO or CS and a second CH₂            is replaced by NR27;            -   z is 1, 2, 3, 4, 5 or 6, wherein the group C_(z)H_(2z+1)                is unsubstituted or substituted where one ore more H                atoms are replaced by F atoms;        -   R27 is H or C_(aa)H_(2aa+1);            -   aa is 1, 2, 3 or 4, wherein the group C_(aa)H_(2aa+1) is                unsubstituted or substituted where one ore more H atoms                are replaced by F atoms;        -   or        -   R27 and a CH₂ group of R25 or R26 together with the N atom            to which they are bonded form a 5- or 6-membered ring;        -   or        -   R25 and R26 together with the N atom to which they are            bonded form a 5- or 6-membered ring,    -   or    -   R7, R8 and R9 are independently of one another NR32COR30,        NR32CSR30 or NR32SO₂R30;        -   R30 is H, OH, C_(cc)H_(2cc+1), C_(yy)H_(2yy−1), pyrrolidinyl            or piperidinyl, wherein the pyrrolidinyl or piperidinyl is            unsubstituted or substituted where a CH₂ group is replaced            by O or NR33;            -   R32 and R33 are H, methyl or CF₃;            -   cc is 1, 2, 3, 4, 5, 6, 7 or 8;            -   yy is 3, 4, 5 or 6; wherein the groups C_(cc)H_(2cc+1)                and C_(yy)H_(2yy−1) independently of one another are                unsubstituted or substituted where one or more H atoms                are replaced by F atoms and/or one or more CH₂ groups                are replaced by NR31 and/or one CH₂ group is replaced by                O                -   R31 is H, methyl, ethyl, CF₃, CH₂CF₃, acetyl or                    propionyl, methanesulfonyl or ethanesulfonyl;                -   or                -   R31 together with a CH₂ group of R30 and the N atom                    to which they are jointly bonded form a 5- or                    6-membered ring;        -   or        -   R30 is pyridyl, imidazolyl, pyrazolyl, triazolyl,            tetrazolyl, thiazolyl or oxazolyl, which are unsubstituted            or substituted by up to 3 substituents chosen from F, Cl,            methyl, ethyl, trifluoromethyl, NH₂, and NHacetyl;    -   or    -   R7, R8 and R9 are independently of one another H, F, Cl, OH,        NH₂, C_(ee)H_(2ee+1), C_(ww)H_(2ww−1), OC_(ff)H_(2ff+1),        NR4OR41, CONR4OR41, COOR42 or OCOR42,        -   ee and ff are independently of one another 1, 2, 3 or 4;            -   ww is 3, 4, 5 or 6, wherein the groups C_(ee)H_(2ee+1),                C_(ww)H_(2ww−1) and OC_(ff)H_(2ff+1) independently of                one another are unsubstituted or substituted where one                or more H atoms are replaced by F atoms;        -   R40 and R41 are H, C_(tt)H_(2tt+1) or C(NH)NH₂;            -   tt is 1, 2, 3 or 4, wherein the group C_(tt)H_(2tt+1) is                unsubstituted or substituted where one or more H atoms                are replaced by F atoms;        -   or        -   R40 and R41 independently of one another are hydroxyethyl,            N,N-dimethylaminoethyl, N,N-diethylaminoethyl,            pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl,            morpholinoethyl or piperidinoethyl;        -   or        -   R40 and R41 together with the N atom to which they are            bonded form a pyrrolidine, piperidine, N-methylpiperazine,            piperazine or morpholine ring;        -   R42 is H or C_(hh)H_(2hh+1);            -   hh is 1, 2, 3 or 4, wherein the C_(hh)H_(2hh+1) is                unsubstituted or substituted where one or more H atoms                are replaced by F atoms;    -   with the proviso that two substituents chosen from the group R7,        R8 and R9 can not simultaneously be OH and OCH₃,    -   and that at least one of the substituents R7, R8 and R9 is        chosen from CONR4OR41, —O_(v)—SO_(w)—R23, NR32COR30, NR32CSR30        and NR32SO_(bb)R30;    -   and the pharmaceutically acceptable salts and trifluoroacetates        thereof.

In another embodiment, compounds of the formula I are chosen from:

-   -   R1, R2, R3 and R4 are independently of one another H, F, Cl, Br,        OH, NH₂, C_(a)H_(2a+1), cycloalkyl with 3, 4, 5 or 6 C atoms, or        OC_(b)H_(2b+1);        -   a and b are independently of one another 1, 2, 3 or 4,            wherein the groups C_(a)H_(2a+1) and OC_(b)H_(2b+1)            independently of one another are unsubstituted or            substituted where one or more H atoms to be replaced by F            atoms;    -   or    -   R1, R2, R3 and R4 are independently of one another NR11 R12;        wherein        -   R11 and R12 are independently of one another H,            C_(e)H_(2e+1), or C_(rr)H_(2rr−1);            -   e is 1, 2, 3 or 4,            -   rr is 3, 4, 5 or 6, wherein the groups C_(e)H_(2e+1) and                C_(rr)H_(2rr−1) independently of one another are                unsubstituted or substituted where one or more H atoms                are replaced by F atoms;        -   or        -   R11 and R12 together with the N atom to which they are            bonded form a ring chosen from pyrrolidine, piperidine,            N-methylpiperazine, piperazine and morpholine;        -   or        -   R11 and R12 are independently of one another COR14, CSR14,            CONHR14, CSNHR14 or SO₂R14;            -   R14 is C_(g)H_(2g+1);                -   g is 1, 2, 3 or 4, wherein the group C_(g)H_(2g+1)                    is unsubstituted or substituted where one or more H                    atoms to be replaced by F atoms;    -   or    -   R1, R2, R3 and R4 are independently of one another OSO₃H, SO₃H,        or SO₂R15;    -   wherein        -   R15 is C_(k)H_(2k+1) or NR17R18;            -   k is 1, 2, 3 or 4, wherein the group C_(k)H_(2k+1) is                unsubstituted or substituted where one or more H atoms                to be replaced by F atoms;            -   R17 and R18 are independently of one another H or                C_(m)H_(2m+1);                -   m is 1, 2, 3, 4 or 5, wherein the group                    C_(m)H_(2m+1) is unsubstituted or substituted where                    one or more H atoms to be replaced by F atoms;            -   or            -   R17 and R18 together with the N atom to which they are                bonded form a 5- or 6-membered ring;    -   but where R2 does not equal H in any of the foregoing        definitions,    -   R5 is methyl or trifluoromethyl;    -   R6 is H;    -   R7, R8 and R9 are independently of one another OSO₃H, SO₃H or        SO₂R₂₃;        -   R23 is C_(nn)H_(2nn+1) or NR25R26;            -   nn is 1, 2, 3, 4 or 5, wherein the group C_(nn)H_(2nn+1)                is unsubstituted or substituted where one or more H                atoms to be replaced by F atoms;        -   R25 and R26 are independently of one another H, CN or            C_(z)H_(2z+1) in which a first CH₂ group bonded to the            nitrogen of NR25R26 is replaced by CO or CS and a second CH₂            is replaced by NR27;            -   z is 1, 2, 3, 4, 5 or 6, wherein the group C_(z)H_(2z+1)                is unsubstituted or substituted where one or more H                atoms to be replaced by F atoms;        -   R27 is H or C_(aa)H_(2aa+1);            -   aa is 1, 2, 3 or 4, wherein the group C_(aa)H_(2aa+1) is                unsubstituted or substituted where one or more H atoms                to be replaced by F atoms;        -   or        -   R27 and a CH₂ group of R25 or R26 together with the N atom            to which they are bonded form a 5- or 6-membered ring;        -   or        -   R25 and R26 together with the N atom to which they are            bonded form a 5- or 6-membered ring,    -   or    -   R7, R8 and R9 are independently of one another NR32COR30,        NR32CSR30 or NR32SO₂R30;        -   R30 is H, OH, C_(cc)H_(2cc+1), C_(yy)H_(2yy−1), pyrrolidinyl            or piperidinyl, wherein the pyrrolidinyl or piperidinyl is            unsubstituted or substituted where a CH₂ group is replaced            by O or NR33;        -   R32 and R33 are independently of one another H, methyl or            CF₃;        -   cc is 1, 2, 3, 4, 5, 6, 7 or 8;        -   yy is 3, 4, 5 or 6; wherein wherein the groups            C_(cc)H_(2cc+1) and C_(yy)H_(2yy−1) independently of one            another are unsubstituted or substituted where one or more H            atoms are replaced by F atoms and/or one or more CH₂ groups            are replaced by NR31 and/or one CH₂ group are replaced by O;            -   R31 is H, methyl, ethyl, CF₃, CH₂CF₃, acetyl or                propionyl, methanesulfonyl or ethanesulfonyl;            -   or            -   R31 together with a CH₂ group of R30 and the N atom to                which they are jointly bonded form a 5- or 6-membered                ring;        -   or        -   R30 is pyridyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl,            tetrazolyl, thiazolyl or oxazolyl, which are unsubstituted            or substituted by up to 3 substituents chosen from F, Cl,            methyl, ethyl, trifluoromethyl, NH₂, and NHacetyl;    -   or    -   R7, R8 and R9 are independently of one another H, F, Cl, OH,        NH₂, C_(ee)H_(2ee+1), C_(ww)H_(2ww−1), OC_(ff)H_(2ff+1),        NR4OR41, CONR4OR41, COOR42 or OCOR42,        -   ee and ff are independently of one another 1, 2, 3 or 4;            -   ww is 3, 4, 5 or 6, wherein the groups C_(ee)H_(2ee+1),                C_(ww)H_(2ww−1) and OC_(ff)H_(2ff+1) independently of                one another are unsubstituted or substituted where one                or more H atoms to be replaced by F atoms;        -   R40 and R41 is H, C_(tt)H_(2tt+1) or C(NH)NH₂;            -   tt is 1, 2, 3 or 4, wherein the group C_(tt)H_(2tt+1) is                unsubstituted or substituted where one or more H atoms                to be replaced by F atoms;        -   or        -   R40 and R41 are independently of one another hydroxyethyl,            N,N-dimethylaminoethyl, N,N-diethylaminoethyl,            pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl,            morpholinoethyl or piperidinoethyl;        -   or        -   R40 and R41 together with the N atom to which they are            bonded form a pyrrolidine, piperidine, N-methylpiperazine,            piperazine or morpholine ring;        -   R42 is H or C_(hh)H_(2hh+1);            -   hh is 1, 2, 3 or 4, wherein the group C_(hh)H_(2hh+1) is                unsubstituted or substituted where one or more H atoms                to be replaced by F atoms;    -   with the proviso that two substituents chosen from the group R7,        R8 and R9 can not simultaneously be OH and OCH₃,    -   and that at least one of the substituents R7, R8 and R9 is        chosen from —O_(v)—SO_(w)—R23, NR32COR30, NR32CSR30 and        NR32SO_(bb)R30;    -   and the pharmaceutically acceptable salts and trifluoroacetates        thereof.

In another embodiment, compounds of the invention are chosen from thefollowing:

-   -   1)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   2)        4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide;    -   3)        3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide;    -   4)        4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N,N-dimethyl-benzenesulfonamide;    -   5)        4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline;    -   6)        4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic        acid;    -   7)        4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-ethyl-benzamide;    -   8)        4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-propyl-benzamide;    -   9)        4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethylamino-ethyl)-benzamide;    -   10)        6,8-dichloro-2-methyl-4-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline;    -   11)        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-phenyl]-diethyl-amine    -   12)        6,8-dichloro-2-methyl-4-(4-piperidin-1-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline;    -   13)        6,8-dichloro-2-methyl-4-(4-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline;    -   14)        6,8-dichloro-2-methyl-4-[4-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-isoquinoline;    -   15)        6,8-dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;    -   16)        4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;    -   17)        1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-propylurea;    -   18)        1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea;    -   19)        1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;    -   20)        N-[4-(6-methanesulfonyl-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   21)        N-[4-(2,6,8-trimethyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   22)        N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   23)        N-[4-(8-chloro-2-methyl-6-pyrrolidin-1-yl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   24)        N-[4-(8-chloro-2-methyl-6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   25)        N-{4-[8-chloro-2-methyl-6-(4-methyl-piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinolin-4-yl]-phenyl}-acetamide;    -   26)        N-{4-[8-chloro-6-(cyclopropylmethyl-amino)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl]-phenyl}-acetamide;    -   27)        5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoic        acid;    -   28)        5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-N-methyl-benzamide;    -   29)        5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-ethyl-2-hydroxy-benzamide;    -   30)        5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethylamino-ethyl)-2-hydroxy-benzamide;    -   31)        N-[5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoyl]-guanidine;    -   32)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   33)        3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;    -   34)        2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;    -   35)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;    -   36)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;    -   37)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]pentanamide;    -   38)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isobutyramide;    -   39)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2-dimethyl-propionamide;    -   40)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopropanecarboxamide;    -   41)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclobutanecarboxamide;    -   42)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopentanecarboxamide;    -   43)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-acetamide;    -   44)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetylpiperidine-4-carboxamide;    -   45)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-nicotinamide;    -   46)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-sulfonamide;    -   47)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-ethanesulfonamide;    -   48)        N′,N′-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-sulfamide;    -   49)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;    -   50)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;    -   51)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pentanamide;    -   52)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isobutyramide;    -   53)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2-dimethyl-propionamide;    -   54)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopropanecarboxamide;    -   55)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclobutanecarboxamide;    -   56)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopentanecarboxamide;    -   57)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-acetamide;    -   58)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetylpiperidine-4-carboxamide;    -   59)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-nicotinamide;    -   60)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-sulfonamide;    -   61)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-ethanesulfonamide;    -   62)        N′,N′-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-sulfamide;    -   63)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;    -   64)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;    -   65)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pentanamide;    -   66)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isobutyramide;    -   67)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2-dimethyl-propionamide;    -   68)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopropanecarboxamide;    -   69)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclobutanecarboxamide;    -   70)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopentanecarboxamide;    -   71)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-acetamide;    -   72)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetylpiperidine-4-carboxamide;    -   73)        N-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-sulfonamide;    -   74)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-ethanesulfonamide;    -   75)        N′,N′-dimethylamino-N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-sulfamide;    -   76)        1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;    -   77)        1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea;    -   78)        1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;    -   79)        1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea;    -   80)        N-{5-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide;    -   81)        N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide;    -   82)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,2-dimethyl-1H-imidazole-4-sulfonamide;    -   83)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,2-dimethyl-1H-imidazole-4-sulfonamide;    -   84)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide;    -   85)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide;    -   86)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-5-bromo-thiophene-2-sulfonamide;    -   87)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-5-bromo-thiophene-2-sulfonamide;    -   88)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C-trifluoro-methanesulfonamide;    -   89)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C-trifluoro-methanesulfonamide;    -   90)        4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoroethanesulfonamide;    -   91)        3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-ethanesulfonamide;    -   92)        N-ethyl-N′-4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonylurea;    -   93)        2-chloro-5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide;    -   94)        2-methyl-4-phenyl-6,8-bis-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline;    -   95)        2-Amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   96)        N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-methylamino-acetamide;    -   97)        N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-dimethylamino-acetamide;    -   98)        2-Amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;    -   99)        2-Amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;    -   100) 2,6-Diamino-hexanoic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   101) Pyrrolidine-2-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   102)        N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isonicotinamide;    -   103) 1H-Pyrrole-3-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   104) 1H-Pyrrole-2-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   105) 1-Methyl-piperidine-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   106) 1,4-Dimethyl-1H-pyrrole-2-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   107) 4-Nitro-1H-pyrrole-2-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   108) 2,5-Dimethyl-1H-pyrrole-3-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   109) 1H-Imidazole-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   110) 1-Methanesulfonyl-piperidine-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   111) 3,5-Dimethyl-1H-pyrazole-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   112) 1H-Pyrazole-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   113) 3-Trifluoromethyl-1H-pyrazole-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   114)        N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-methylamino-acetamide;    -   115)        N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-dimethylamino-acetamide;    -   116)        2-Amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;    -   117)        2-Amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;    -   118) 2,6-Diamino-hexanoic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   119) Pyrrolidine-2-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   120)        N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isonicotinamide;    -   121) 1H-Pyrrole-3-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   122) 1H-Pyrrole-2-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   123) 1-Methyl-piperidine-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   124) 1,4-Dimethyl-1H-pyrrole-2-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   125) 4-Nitro-1H-pyrrole-2-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   126) 2,5-Dimethyl-1H-pyrrole-3-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   127) 1H-Imidazole-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   128)1-Methanesulfonyl-piperidine-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   129) 3,5-Dimethyl-1H-pyrazole-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   130) 1H-Pyrazole-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   131) 3-Trifluoromethyl-1H-pyrazole-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   132)        1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-thiourea;    -   133)        1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-thiourea;    -   134)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-thiourea;    -   135)        3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-dimethyl-urea;    -   136) 4-Methyl-piperazine-1-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   137) Piperidine-1-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   138) Morpholine-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   139) Pyrrolidine-1-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   140)        3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-diethyl-urea;    -   141)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea;    -   142)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea;    -   143)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(tetrahydro-furan-3-yl)-urea;    -   144)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(tetrahydro-pyran-4-yl)-urea;    -   145)        3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methyl-1-(1-methyl-piperidin-4-yl)-urea;    -   146)        3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-(3-dimethylamino-propyl)-1-methyl-urea;    -   147)        3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-(2-dimethylamino-ethyl)-1-methyl-urea;    -   148)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(3-dimethylamino-propyl)-urea;    -   149)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-methoxy-ethyl)-urea;    -   150)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin-3-yl-urea;    -   151)1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin-4-yl-urea;    -   152) 4-Methyl-piperazine-1-carboxylic acid        [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   153)        1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea;    -   154)        3-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-dimethyl-urea;    -   155)        3-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-diethyl-urea;    -   156) Piperidine-1-carboxylic acid        [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   157) Morpholine-4-carboxylic acid        [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   158) Pyrrolidine-1-carboxylic acid        [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   159)        1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea;    -   160) 4-Methyl-piperazine-1-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   161) Pyrrolidine-1-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   162)1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea;    -   163)        3-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-dimethyl-urea;    -   164)        3-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-diethyl-urea;    -   165)        1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea;    -   166) Piperidine-1-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   167) Morpholine-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   168)        N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-formamide;    -   169)        [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine;    -   170)        1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3-dimethyl-urea;    -   171) 4-Methyl-piperazine-1-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide;    -   172)        1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3-trimethyl-urea;    -   173) Piperidine-1-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide;    -   174) Morpholine-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide;    -   175) Pyrrolidine-1-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide;    -   176)        1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-1-methyl-urea;    -   177)        1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,3-diethyl-1-methyl-urea;    -   178)        N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-formamide;    -   179)        [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine;    -   180) Pyrrolidine-1-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide;    -   181) Piperidine-1-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide;    -   182)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3-trimethyl-urea;    -   183)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3-dimethyl-urea;    -   184) Morpholine-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide;    -   185) 4-Methyl-piperazine-1-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide;    -   186)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-1-methyl-urea;    -   187)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,3-diethyl-1-methyl-urea;    -   188)        [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid 2-dimethylamino-ethyl ester;    -   189)        [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid 2-dimethylamino-ethyl ester;    -   190)        [2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid 2-dimethylamino-ethyl ester;    -   191)        [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid methyl ester;    -   192)        [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid ethyl ester;    -   193)        [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid isopropyl ester;    -   194)        [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid 2,2-dimethyl-propyl ester;    -   195)        [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid methyl ester;    -   196)        [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid isopropyl ester;    -   197)        [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid 2,2-dimethyl-propyl ester;    -   198)        [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid ethyl ester;    -   199)        (+)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide;    -   200)        (−)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide;    -   201)        (+)-1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;    -   202)        (−)-1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;    -   203)        N-[3-(6,8-Difluoro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   204)        4-(3-Bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline;    -   205)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-hydroxy-ethyl)-urea;    -   206)        3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic        acid ethyl ester; and    -   207)        3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic        acid        and the pharmaceutically acceptable salts thereof.

In another embodiment, compounds of the invention are chosen from thefollowing:

-   -   1)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   2)        4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide;    -   3)        3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide;    -   4)        1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea;    -   5)        1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;    -   6)        N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   7)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   8)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;    -   9)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetyl-piperidine-4-carboxamide;    -   10)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-sulfonamide;    -   11)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-ethanesulfonamide;    -   12)        N′,N′-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-sulfamide;    -   13)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;    -   14)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;    -   15)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isobutyramide;    -   16)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopropanecarboxamide;    -   17)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclobutanecarboxamide;    -   18)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-acetamide;    -   19)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetyl-piperidine-4-carboxamide;    -   20)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-nicotinamide;    -   21)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-sulfonamide;    -   22)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-ethanesulfonamide;    -   23)        N′,N′-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-sulfamide;    -   24)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopropanecarboxamide;    -   25)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetyl-piperidine-4-carboxamide;    -   26)        1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;    -   27)        1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea;    -   28)        1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;    -   29)        1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea;    -   30)        N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide;    -   31)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,2-dimethyl-1H-imidazole-4-sulfonamide;    -   32)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C-trifluoro-methanesulfonamide;    -   33)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C-trifluoro-methanesulfonamide;    -   34)        N-ethyl-N′-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonylurea;    -   35)        N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-dimethylamino-acetamide;    -   36) 2,6-Diamino-hexanoic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   37) 1H-Pyrrole-3-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   38) 1-Methyl-piperidine-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   39) 1-Methanesulfonyl-piperidine-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   40) 1H-Pyrazole-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   41)        N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-methylamino-acetamide;    -   42)        N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-dimethylamino-acetamide;    -   43)        2-Amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;    -   44)        2-Amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;    -   45) 2,6-Diamino-hexanoic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   46) 1-Methyl-piperidine-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   47) 1H-Imidazole-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   48) 1-Methanesulfonyl-piperidine-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   49) 3,5-Dimethyl-1H-pyrazole-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   50) 1H-Pyrazole-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   51)        3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-dimethyl-urea;    -   52) 4-Methyl-piperazine-1-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   53) Piperidine-1-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   54) Morpholine-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   55) Pyrrolidine-1-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   56)        3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-diethyl-urea;    -   57)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea;    -   58)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea;    -   59)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(tetrahydro-furan-3-yl)-urea;    -   60)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(tetrahydro-pyran-4-yl)-urea;    -   61)        3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methyl-1-(1-methyl-piperidin-4-yl)-urea;    -   62)        3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-(3-dimethylamino-propyl)-1-methyl-urea;    -   63)        3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-(2-dimethylamino-ethyl)-1-methyl-urea;    -   64)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(3-dimethylamino-propyl)-urea;    -   65)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-methoxy-ethyl)-urea;    -   66)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin-3-yl-urea;    -   67)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin-4-yl-urea;    -   68) 4-Methyl-piperazine-1-carboxylic acid        [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   69)        1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea;    -   70)        1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea;    -   71) 4-Methyl-piperazine-1-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   72)        1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea;    -   73)        3-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-dimethyl-urea;    -   74)        3-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-diethyl-urea;    -   75)        1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea;    -   76) Morpholine-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   77)        N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-formamide;    -   78)        N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-formamide;    -   79)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3-trimethyl-urea;    -   80)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3-dimethyl-urea;    -   81) Morpholine-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide;    -   82) 4-Methyl-piperazine-1-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide;    -   83)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-1-methyl-urea;    -   84)        [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid 2-dimethylamino-ethyl ester;    -   85)        [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid 2-dimethylamino-ethyl ester;    -   86)        [2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid 2-dimethylamino-ethyl ester;    -   87)        [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid methyl ester;    -   88) (R or        S)—N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide;    -   89) (R or        S)-1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;        and    -   90)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-hydroxy-ethyl)-urea;        and the pharmaceutically acceptable salts thereof.

In one embodiment, the invention encompasses the use of the compounds ofthe formula I for the treatment of disorders which can be influenced byinhibition of the sodium-proton exchange of subtype III (NHE3), inwhich:

-   -   wherein:    -   R1, R2, R3 and R4 are independently of one another H, F, Cl, Br,        I, CN, NO₂, OH, NH₂, C_(a)H_(2a+1), C_(qq)H_(2qq−1),        OC_(b)H_(2b+1), COOR10, OCOR10, COR10 or O_(x)—(CH₂)_(y)-phenyl;        wherein        -   a and b are independently of one another 1, 2, 3, 4, 5, 6, 7            or 8, wherein the groups C_(a)H_(2a+1) and OC_(b)H_(2b+1)            independently of one another are unsubstituted or            substituted where one or more H atoms are replaced by F            atoms;        -   qq is 3, 4, 5, 6, 7 or 8, wherein the group CqqH2qq−1 is            unsubstituted or substituted where one or more H atoms are            replaced by F atoms;        -   R10 is H or C_(c)H_(2c+1);            -   c is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group CcH2c+1                is unsubstituted or substituted where one or more H                atoms are replaced by F atoms;        -   x is zero or 1;        -   y is zero, 1, 2, 3 or 4; where the phenyl ring in the group            O_(x)—(CH₂)_(y)-phenyl is unsubstituted or substituted by            1-3 independently chosen from F, Cl, Br, CN, NO₂, OH, NH₂            and C_(d)H_(2d+1),            -   d is 1, 2, 3 or 4, wherein the group C_(d)H_(2d+1) is                unsubstituted or substituted where one or more H atoms                are replaced by F atoms;    -   or    -   R1, R2, R3 and R4 are independently of one another chosen from a        heteroaryl with at least one heteroatom chosen from 1, 2, 3 or 4        N atoms, 1 oxygen atom and 1 S atom, present as ring atoms;    -   or    -   R1, R2, R3 and R4 are independently of one another CONR11R12 or        NR11R12;    -   wherein        -   R11 and R12 are independently of one another H,            C_(e)H_(2e+1), C_(rr)H_(2rr−1);            -   e is 1, 2, 3, 4, 5, 6, 7 or 8;            -   rr is 3, 4, 5, 6, 7, or 8, wherein the groups                C_(e)H_(2e+1) and C_(rr)H_(2rr−1) independently of one                another are unsubstituted or substituted where one or                more H atoms are replaced by F atoms and/or one or more                CH₂ groups are replaced by O or NR13;                -   R13 is H or C_(f)H_(2f+1);                -    f is 1, 2, 3 or 4, wherein the group C_(f)H_(2f+1)                    is unsubsitituted or substituted where one or more H                    atoms are replaced by F atoms;                -   or                -   R13 and a CH₂ group of R11 or R12 together with the                    N atom to which they are bonded form a 5- or                    6-membered ring;        -   or        -   R11 and R12 together with the N atom to which they are            bonded form a 5-, 6- or 7-membered ring;        -   or        -   R11 and R12 are independently of one another COR14, CSR14 or            SO₂R14;        -   wherein            -   R14 is C_(g)H_(2g+1);                -   g is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group                    C_(g)H_(2g+1) is unsubsitituted or substituted where                    one or more H atoms are replaced by F atoms, and/or                    one or more CH₂ groups are replaced by O or NR13;    -   or    -   R1, R2, R3 and R4 are independently of one another        —O_(h)—SO_(j)—R15, with        -   h is zero or 1;        -   j is zero, 1 or 2;        -   R15 is C_(k)H_(2k+1), OH, OC_(l)H_(2l+1) or NR17R18;            -   k is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group                C_(k)H_(2k+1) is unsubsitituted or substituted where one                or more H atoms are replaced by F atoms;            -   l is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group                OC_(l)H_(2l+1) is unsubsitituted or substituted where                one or more H atoms are replaced by F atoms;            -   R17 and R18 are independently of one another H or                C_(m)H_(2m+1);                -   m is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group                    C_(m)H_(2m+1) is unsubstituted or substituted where                    one or more H atoms is replaced by F atoms and/or                    one or more CH₂ groups are replaced by O, CO, CS or                    NR19;                -    R19 is H or C_(n)H_(2n+1);                -    n is 1, 2, 3 or 4, wherein the group C_(n)H_(2n+1)                    is unsubstituted or substituted where one or more H                    atoms are replaced by F atoms;                -    or                -    R19 and a CH₂ group of R17 or R18 together with the                    N atom to which they are bonded form a 5- or                    6-membered ring;            -   or            -   R17 and R18 together with the N atom to which they are                bonded form a 5-, 6- or 7-membered ring;    -   R5 is H, C_(p)H_(2p+1), C_(ss)H_(2ss−1), COR20 or SO₂R20;        wherein        -   p is 1, 2, 3, 4, 5, 6, 7 or 8,        -   ss is 3, 4, 5, 6, 7 or 8,        -   R20 is C_(q)H_(2q+1);            -   q is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the groups                C_(p)H_(2p+1), C_(ss)H_(2ss−1) and C_(q)H_(2q+1)                independently of one another are unsubstituted or                substituted where one or more H atoms are replaced by F                atoms and/or one or more CH₂ groups are replaced by O or                NR21;            -   R21 is H or C_(r)H_(2r+1);                -   r is 1, 2, 3 or 4; wherein the group C_(r)H_(2r+1)                    is unsubstituted or substituted where one or more H                    atoms are replaced by F atoms;    -   R6 is H, F, Cl, Br, I, C_(s)H_(2s+1), C_(dd)H_(2dd−1), OH,        OC_(t)H_(2t+1) or OCOR22; wherein        -   s and t are independently of one another 1, 2, 3, 4, 5, 6, 7            or 8;        -   dd is 3, 4, 5, 6, 7 or 8, wherein the groups C_(s)H_(2s+1),            C_(dd)H_(2dd−1) and OC_(t)H_(2t+1) independently of one            another are unsubstituted or substituted where one or more H            atoms are replaced by F atoms;        -   R22 is C_(u)H_(2u+1);            -   u 1, 2, 3 or 4, wherein the group C_(u)H_(2u+1) is                unsubstituted or substituted where one or more H atoms                are replaced by F atoms;    -   R7, R8 and R9 are independently of one another        —O_(v)—SO_(w)—R23; wherein        -   v is zero or 1;        -   w is zero, 1 or 2;        -   R23 is C_(nn)H_(2nn+1), C_(mm)H_(2mm−1), OH,            OC_(pp)H_(2pp+1) or NR25R26;            -   nn and pp are independently of one another 1, 2, 3, 4,                5, 6, 7 or 8,            -   mm is 3, 4, 5, 6, 7 or 8, wherein the groups                C_(nn)H_(2nn+1),            -   C_(mm)H_(2mm−1) and OC_(pp)H_(2pp+1) independently of                one another are unsubstituted or substituted where one                or more H atoms are replaced by F atoms;            -   R25 and R26 are independently of one another H, CN,                C_(z)H_(2z+1), or C_(zz)H_(2zz−1);                -   z is 1, 2, 3, 4, 5, 6, 7 or 8;                -   zz is 3, 4, 5, 6, 7 or 8, wherein the group                    C_(z)H_(2z+1) is unsubstituted or substituted where                    one or more H atoms are replaced by F atoms and,                    wherein the group C_(z)H_(2z+1), is unsubstituted or                    substituted where one or more H atoms are replaced                    by F atoms and/or one or more CH₂ groups are                    replaced by O, CO, CS or NR27;                -   R27 is H or C_(aa)H_(2aa+1);                -    aa is 1, 2, 3 or 4, wherein the group                    C_(aa)H_(2aa+1) is unsubstituted or substituted                    where one or more H atoms are replaced by F atoms;                -   or                -   R27 and a CH₂ group of R25 or R26 together with the                    N atom to which they are bonded form a 5- or                    6-membered ring;            -   or            -   R25 and R26 together with the N atom to which they are                bonded form a 5-, 6- or 7-membered ring;    -   or    -   R7, R8 and R9 are independently of one another NR32COR30,        NR32CSR30 or NR32SO_(bb)R30;        -   R30 is H, C_(cc)H_(2cc+1), C_(yy)H_(2yy−1), pyrrolidinyl or            piperidinyl, wherein the pyrrolidinyl or piperidinyl is            unsubstituted or substituted where a CH₂ group is replaced            by O or NR33;        -   R32 and R33 are independently of one another H or            C_(h)H_(2h+1);        -   bb is 2 or 3;        -   cc is 1, 2, 3, 4, 5, 6, 7 or 8;        -   yy is 3, 4, 5, 6, 7 or 8;        -   h is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group            C_(h)H_(2h+1) is unsubstituted or substituted where one or            more H atoms are replaced by F atoms, and whrein the groups            C_(cc)H_(2cc+1) and C_(yy)H_(2yy−1) independently of one            another are unsubstituted or substituted where one or more H            atoms are replaced by F atoms and/or one or more CH₂ groups            are replaced by NR31 and/or one CH₂ group are replaced by O;        -   R31 is H, C_(kk)H_(2kk+1), COR65 or SO₂ R65;            -   kk is 1, 2, 3, or 4; wherein the group C_(kk)H_(2kk+1)                is unsubstituted or substituted where one or more H                atoms are replaced by F atoms,            -   R65 is H, or C_(xx)H_(2xx+1);            -   xx is 1, 2, 3 or 4, wherein the group C_(xx)H_(2xx+1) is                unsubstituted or substituted where one or more H atoms                are replaced by F atoms;        -   or        -   R31 together with a CH₂ group of R30 forms a 5-, 6- or            7-membered ring;        -   or        -   R30 is a 5- or 6-membered heteroaryl with at least one            hetero atom chosen from 1, 2, 3 or 4 N atoms, zero, 1 S atom            and 1 O atom,            -   which is unsubstituted or substituted by up to three                substituents chosen from F, Cl, Br, I, C_(oo)H_(2oo+1),                and NR70R71;            -   R70 and R71 are independently of one another H,                C_(uu)H_(2uu+1) or COR72;                -   R72 is H, or C_(vv)H_(2vv+1);                -   oo, uu and w are independently of one another 1, 2,                    3, 4, 5, 6, 7 or 8, wherein the groups                    C_(oo)H_(2oo+1), C_(uu)H_(2uu+1) and C_(vv)H_(2vv+1)                    independently of one another are unsubstituted or                    substituted where one or more H atoms are replaced                    by F atoms;    -   or    -   R7, R8 and R9 are independently of one another H, F, Cl, Br, I,        NO₂, CN, OH, NH₂, C_(ee)H_(2ee+1), C_(ww)H_(2ww−1),        OC_(ff)H_(2ff+1), NR40R41, CONR40R41, COOR42, COR42 or OCOR42,        -   ee and ff are independently of one another 1, 2, 3, 4, 5, 6,            7 or 8;        -   ww is 3, 4, 5, 6, 7 or 8, wherein the groups            C_(ee)H_(2ee+1), C_(ww)H_(2ww−1) and OC_(ff)H_(2ff+1)            independently of one another are unsubstituted or            substituted where one or more H atoms are replaced by F            atoms;        -   R40 and R41 are independently of one another H,            C_(tt)H_(2tt+1) or C(NH)NH₂;            -   tt is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group                C_(tt)H_(2tt+1) is unsubstituted or substituted where                one or more H atoms are replaced by F atoms and/or where                one or more CH₂ groups are replaced by O or NR44;            -   R44 is H or C_(gg)H_(2gg+1);                -   gg is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group                    C_(gg)H_(2gg+1) is unnsubstituted or substituted                    where one or more H atoms are replaced by F atoms            -   or            -   R44 forms a 5- or 6-membered ring together with a (CH₂)                group of R40 or R41 and the N atom to which they are                bound;        -   or        -   R40 and R41 with the N atom to which they are bonded form a            5- or 6-membered ring;        -   R42 is H or C_(hh)H_(2hh+1);            -   hh is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group                C_(hh)H_(2hh+1) is unnsubstituted or substituted where                one or more H atoms are replaced by F atoms;    -   and the pharmaceutically acceptable salts thereof.

In another embodiment, the use of the compounds of the formula I for thetreatment of disorders which can be influenced by inhibition of thesodium-proton exchange of subtype III (NHE3), are chosen from:

-   -   R1, R2, R3 and R4 are independently of one another, H, F, Cl,        Br, I, CN, NO₂, OH,    -   NH₂, C_(a)H_(2a+1), cycloalkyl with 3, 4, 5 or 6 C atoms,        OC_(b)H_(2b+1), or COOR10;    -   wherein        -   a and b are independently of one another 1, 2, 3 or 4,            wherein the group C_(a)H_(2a+1) is unsubstituted or            substituted where one or more H atoms are replaced by F            atoms;        -   R10 is H or C_(c)H_(2c+1);        -   c is 1, 2, 3 or 4, wherein the group C_(c)H_(2c+)1 is            unsubstituted or substituted where one or more H atoms are            replaced by F atoms;        -   or    -   R1, R2, R3 and R4 are independently of one another a 5- or        6-membered heteroaryl choawn from pyridyl, imidazolyl,        pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl and        oxazolyl;    -   or    -   R1, R2, R3 and R4 are independently of one another CONR11R12 or        NR11R12;    -   wherein        -   R11 and R12 are independently of one another H,            C_(e)H_(2e+1), C_(rr)H_(2rr−1);            -   e is 1, 2, 3 or 4,            -   rr is 3, 4, 5 or 6, wherein the groups C_(e)H_(2e+1) and                C_(rr)H_(2rr−1) independently of one another are                unsubstituted or substituted where one or more H atoms                are replaced by F atoms;        -   or        -   R11 and R12 independently of one another are hydroxyethyl,            N,N-dimethylaminoethyl, N,N-diethylaminoethyl,            pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl,            morpholinoethyl or piperidinoethyl;        -   or        -   R11 and R12 together with the N atom to which they are            bonded form a pyrrolidine, piperidine, N-methylpiperazine,            piperazine or morpholine ring;        -   or        -   R11 and R12 are independently of one another COR14, CSR14,            CONHR14, CSNHR14 or SO₂R14; wherein            -   R14 is C_(g)H_(2g+1);                -   g is 1, 2, 3 or 4, wherein the group C_(g)H_(2g+1)                    is unsbustituted or substituted where one or more H                    atoms are replaced by F atoms;    -   or    -   R1, R2, R3 and R4 are independently of one another OSO₃H, SO₃H,        SO₂R₁₅;    -   wherein        -   R15 is C_(k)H_(2k+1), OC_(l)H_(2l+1) or NR17R18;            -   k is 1, 2, 3 or 4, wherein the group C_(k)H_(2k+1) is                unsubstituted or substituted where one ore more H atoms                are replaced by F atoms;            -   l is 1, 2, 3 or 4, wherein the group OC_(l)H_(2l+1) is                unsubstituted or substituted where one ore more H atoms                are replaced by F atoms;            -   R17 and R18 are independently of one another H, or                C_(m)H_(2m+1), in which the first CH₂ group bonded to                the nitrogen of NR17R18 is replaced by CO and the second                CH₂ group is replaced by NR19;                -   m 1, 2, 3, 4 or 5, wherein the group C_(m)H_(2m+1)                    is unsubstituted or substituted where one or more H                    atoms is replaced by F atoms;                -   R19 is H or C_(n)H_(2n+1);                -    n is 1, 2, 3 or 4, wherein the group C_(n)H_(2n+1)                    is unsubstituted or substituted where one or more H                    atoms is replaced by F atoms;            -   or            -   R17 and R18 together with the N atom to which they are                bonded form a 5- or 6-membered ring;    -   R5 is H, C_(p)H_(2p+1) or C_(ss)H_(2ss−1);        -   p is 1, 2, 3 or 4,        -   ss is 3, 4, 5 or 6, wherein the groups C_(p)H_(2p+1) and            C_(ss)H_(2ss−1) independently of one another are            unsubstituted or substituted where one or more H atoms is            replaced by F atoms;    -   R6 is H, C_(s)H_(2s+1), OC_(t)H_(2t+1) or OCOR22;        -   s and t are independently of one another 1, 2, 3 or 4,            wherein the groups C_(s)H_(2s+1) and OC_(t)H_(2t+1)            independently of another are unsubstituted or substituted            where one or more H atoms is replaced by F atoms;        -   R22 is C_(u)H_(2u+1);            -   u is 1, 2, 3 or 4; wherein the group C_(u)H_(2u+1) is                unsubstituted or substituted where one or more H atoms                is replaced by F atoms;    -   R7, R8 and R9 are independently of one another OSO₃H, SO₃H or        SO₂R23;    -   wherein        -   R23 is C_(nn)H_(2nn+1), C_(mm)H_(2mm−1), OC_(pp)H_(2pp+1) or            NR25R26;            -   nn and pp are independently of one another 1, 2, 3, 4 or                5,            -   mm is 3, 4, 5 or 6, wherein the groups C_(nn)H_(2nn+1),                C_(mm)H_(2mm−1) and OC_(pp)H_(2pp+1) independently of                another are unsubstituted or substituted where one or                more H atoms is replaced by F atoms;        -   R25 and R26 are independently of one another H, CN, or            C_(z)H_(2z+1), in which a first CH₂ group bonded to the            nitrogen of NR25R26 is replaced by CO or CS and a second CH₂            is replaced by NR27;            -   z is 1, 2, 3, 4, 5 or 6; wherein the group C_(z)H_(2z+1)                is unsubstituted or substituted where one or more H                atoms are replaced by F atoms;            -   R27 is H or C_(aa)H_(2aa+1);                -   aa is 1, 2, 3 or 4, wherein the group                    C_(aa)H_(2aa+1) is unsubstituted or substituted                    where one or more H atoms are replaced by F atoms;            -   or            -   R27 and a CH₂ group of R25 or R26 together with the N                atom to which they are bonded form a 5- or 6-membered                ring;        -   or        -   R25 and R26 together with the N atom to which they are            bonded form a 5- or 6-membered ring;    -   or    -   R7, R8 and R9 are independently of one another NR32COR30,        NR32CSR30 or NR32SO₂R30; wherein        -   R30 is H, OH, C_(cc)H_(2cc+1), C_(yy)H_(2yy−1), pyrrolidinyl            or piperidinyl, wherein the pyrrolidinyl or piperidinyl is            unsubstituted or substituted where a CH₂ group is replaced            by O or NR33;        -   R32 and R33 are independently of one another H or            C_(h)H_(2h+1);            -   cc is 1, 2, 3, 4, 5, 6, 7 or 8;            -   yy is3,4,5or6;            -   h is 1, 2, 3 or 4; wherein the group C_(h)H_(2h+1) is                unsubstituted or substituted where one or more H atoms                are replaced by F atoms, and            -   wherein the groups C_(cc)H_(2cc+1) and C_(yy)H_(2yy−1)                independently of one another are unsubstituted or                substituted where one or more H atoms are replaced by F                atoms and/or one or more CH₂ groups to be replaced by                NR31 and/or one CH₂ group to be replaced by O;                -   R31 is H, C_(kk)H_(2kk+1), COR65 or SO₂ R65;                -   kk is 1, 2, 3, or 4, wherein the group                    C_(kk)H_(2kk+1) is unsubstituted or substituted                    where one or more H atoms are replaced by F atoms,                -   R65 is H, or C_(xx)H_(2xx+1);                -   xx is 1, 2, 3 or 4, wherein the group                    C_(xx)H_(2xx+1) is unsubstituted where one or more H                    atoms are replaced by F atoms;        -   or            -   R31 together with a CH₂ group of R30 and the N atom to                which they are jointly bonded form form a 5- or                6-membered ring;        -   or        -   R30 is a 5- or 6-membered heteroaryl chosen from pyridyl,            imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl,            thienyl, thiazolyl and oxazolyl,            -   which is unsubstituted or substituted by up to three                substituents chosen from F, Cl, Br, I, C_(oo)H_(2oo+1),                and NR7OR71,            -   R70 and R71 are independently of one another H,                C_(uu)H_(2uu+1) or COR72;                -   R72 is H, or C_(vv)H_(2vv+1);            -   oo, uu and w are independently of one another 1, 2, 3 or                4, wherein the groups C_(oo)H_(2oo+1), C_(uu)H_(2uu+1)                and C_(vv)H_(2vv+1) independently of one another are                unsubstituted or substituted where one or more H atoms                are replaced by F atoms;    -   or    -   R7, R8 and R9 are independently of one another H, F, Cl, Br, I,        NO₂, CN, OH, NH₂, C_(ee)H_(2ee+1), C_(ww)H_(2ww−1),        OC_(ff)H_(2ff+1), NR40R41, CONR40R41, COOR42, COR42 or OCOR42;        -   ee and ff are independently of one another 1, 2, 3 or 4;        -   ww is 3, 4, 5 or 6, wherein the groups C_(ee)H_(2ee+1),            C_(ww)H_(2ww−1) and OC_(ff)H_(2ff+1) independently of one            another are unsubstituted or substituted where one or more H            atoms are replaced by F atoms;        -   R40 and R41 are independently of one another H,            C_(tt)H_(2tt+1), or C(NH)NH₂;            -   tt is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group                C_(tt)H_(2tt+1) is unsubstituted or substituted where                one or more H atoms are replaced by F atoms;        -   or        -   R40 and R41 are independently of one another chosen from            hydroxyethyl, N, N-dimethylaminoethyl, N,            N-diethylaminoethyl, pyrrolidinoethyl,            N-methylpiperazinoethyl, piperazinoethyl, morpholinoethyl            and piperidinoethyl;        -   or        -   R40 and R41 together with the N atom to which they are            bonded form a ring chosen from pyrrolidine, piperidine,            N-methylpiperazine, piperazine and morpholine;        -   R42 is H or C_(hh)H_(2hh+1);            -   hh is 1, 2, 3 or 4, wherein the group C_(hh)H_(2hh+1) is                unsubstituted or substituted where one or more H atoms                are replaced by F atoms;    -   and the pharmaceutically acceptable salts thereof.

In one embodiment, the use of the compounds of the formula I for thetreatment of disorders which can be influenced by inhibition of thesodium-proton exchange of subtype III (NHE3), are chosen from:

-   -   R1, R2, R3 and R4 are independently of one another H, F, Cl, Br,        OH, NH₂,    -   C_(a)H_(2a+1), cycloalkyl with 3, 4, 5 or 6 C atoms, or        OC_(b)H_(2b+1); wherein        -   a and b are independently of one another 1, 2, 3 or 4,            wherein the groups C_(a)H_(2a+1) and OC_(b)H_(2b+1)            independenly of one another are unsubstituted or substituted            where one or more H atoms are replaced by F atoms;    -   or    -   R1, R2, R3 and R4 are independently of one another NR11R12;        -   R11 and R12 are independently of one another H,            C_(e)H_(2e+1), or C_(rr)H_(2rr−1);            -   e is 1, 2, 3 or 4,            -   rr is 3, 4, 5 or 6, wherein the groups C_(e)H_(2e+1) and                C_(rr)H_(2rr−1) independenly of one another are                unsubtituted or substituted where one or more H atoms                are replaced by F atoms;        -   or        -   R11 and R12 together with the N atom to which they are            bonded form a ring chosen from pyrrolidine, piperidine,            N-methylpiperazine, piperazine and morpholine;        -   or        -   R11 and R12 are independently of one another COR14, CSR14,            CONHR14, CSNHR14 or SO₂R14; wherein            -   R14 is C_(g)H_(2g+1);                -   g is 1, 2, 3 or 4, wherein the group C_(g)H_(2g+1)                    is unsubstituted or substituted where one or more H                    atoms are replaced by F atoms;    -   or    -   R1, R2, R3 and R4 are independently of one another OSO₃H, SO₃H,        or SO₂R15;        -   R15 is C_(k)H_(2k+1) or NR17R18;            -   k is 1, 2, 3 or 4, wherein the group C_(k)H_(2k+1) is                unsubstituted or substituted where one or more H atoms                are replaced by F atoms;            -   R17 and R18 are independently of one another H or                C_(m)H_(2m+1);                -   m is 1, 2, 3, 4 or 5, wherein the group                    C_(m)H_(2m+1) is unsubstituted or substituted where                    one ore more H atoms are replaced by F atoms;            -   or            -   R17 and R18 together with the N atom to which they are                bonded form a 5- or 6-membered ring;    -   but where R2 does not equal H in any of the foregoing        definitions;    -   R5 is methyl or trifluoromethyl;    -   R6 is H;    -   R7, R8 and R9 are independently of one another OSO₃H, SO₃H Or        SO₂R23;    -   wherein        -   R23 is C_(nn)H_(2nn+1) or NR25R26;            -   nn is 1, 2, 3, 4 or 5, wherein the group C_(nn)H_(2nn+1)                is unsubstituted or substituted where one ore more H                atoms are replaced by F atoms;        -   R25 and R26 are independently of one another H, CN or            C_(z)H_(2z+1) in which a first CH₂ group bonded to the            nitrogen of NR25R26 is replaced by CO or CS and a second CH₂            is replaced by NR27;            -   z is 1, 2, 3, 4, 5 or 6, wherein the group C_(z)H_(2z+1)                is unsubstituted or substituted where one ore more H                atoms are replaced by F atoms;        -   R27 is H or C_(aa)H_(2aa+1);            -   aa is 1, 2, 3 or 4, wherein the group C_(aa)H_(2aa+1) is                unsubstituted or substituted where one ore more H atoms                are replaced by F atoms;        -   or        -   R27 and a CH₂ group of R25 or R26 together with the N atom            to which they are bonded form a 5- or 6-membered ring;        -   or        -   R25 and R26 together with the N atom to which they are            bonded form a 5- or 6-membered ring,    -   or    -   R7, R8 and R9 are independently of one another NR32COR30,        NR32CSR30 or NR32SO₂R30;        -   R30 is H, OH, C_(cc)H_(2cc+1), C_(yy)H_(2yy−1), pyrrolidinyl            or piperidinyl, wherein the pyrrolidinyl or piperidinyl is            unsubstituted or substituted where a CH₂ group is replaced            by O or NR33;            -   R32 and R33 are H, methyl or CF₃;            -   cc is 1, 2, 3, 4, 5, 6, 7 or 8;            -   yy is 3, 4, 5 or 6;            -   wherein the groups C_(cc)H_(2cc+1) and C_(yy)H_(2yy−1)                independently of one another are unsubstituted or                substituted where one or more H atoms are replaced by F                atoms and/or one or more CH₂ groups are replaced by NR31                and/or one CH₂ group is replaced by O            -   R31 is H, methyl, ethyl, CF₃, CH₂CF₃, acetyl or                propionyl, methanesulfonyl or ethanesulfonyl;            -   or            -   R31 together with a CH₂ group of R30 and the N atom to                which they are jointly bonded form a 5- or 6-membered                ring;        -   or        -   R30 is pyridyl, imidazolyl, pyrazolyl, triazolyl,            tetrazolyl, thiazolyl or oxazolyl, which are unsubstituted            or substituted by up to 3 substituents chosen from F, Cl,            methyl, ethyl, trifluoromethyl, NH₂, and NHacetyl;    -   or    -   R7, R8 and R9 are independently of one another H, F, Cl, OH,        NH₂, C_(ee)H_(2ee+1), C_(ww)H_(2ww−1), OC_(ff)H_(2ff+1),        NR40R41, CONR40R41, COOR42 or OCOR42,        -   ee and ff are independently of one another 1, 2, 3 or 4;            -   ww is 3, 4, 5 or 6, wherein the groups C_(ee)H_(2ee+1)                C_(ww)H_(2ww−1) and OC_(ff)H_(2ff+1) independently of                one another are unsubstituted or substituted where one                or more H atoms are replaced by F atoms;        -   R40 and R41 are H, C_(tt)H_(2tt+1) or C(NH)NH₂;            -   tt is 1, 2, 3 or 4, wherein the group C_(tt)H_(2tt+1) is                unsubstituted or substituted where one or more H atoms                are replaced by F atoms;        -   or        -   R40 and R41 independently of one another are hydroxyethyl,            N,N-dimethylaminoethyl, N,N-diethylaminoethyl,            pyrrolidinoethyl, N-methylpiperazinoethyl, piperazinoethyl,            morpholinoethyl or piperidinoethyl;        -   or        -   R40 and R41 together with the N atom to which they are            bonded form a pyrrolidine, piperidine, N-methylpiperazine,            piperazine or morpholine ring;        -   R42 is H or C_(hh)H_(2hh+1);            -   hh is 1, 2, 3 or 4, wherein the C_(hh)H_(2hh+1) is                unsubstituted or substituted where one or more H atoms                are replaced by F atoms;    -   and the pharmaceutically acceptable salts thereof.

In another embodiment, the invention encompasses the use of thecompounds of the formula I for the treatment of disorders which can beinfluenced by inhibition of the sodium-proton exchange of subtype III(NHE3), chosen from:

-   -   1)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   2)        4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide;    -   3)        3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide;    -   4)        4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N,        N-dimethyl-benzenesulfonamide;    -   5)        4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline;    -   6)        4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic        acid;    -   7)        4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-ethyl-benzamide;    -   8)        4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-propyl-benzamide;    -   9)        4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethylamino-ethyl)-benzamide;    -   10)        6,8-dichloro-2-methyl-4-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline;    -   11)        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-phenyl]-diethyl-amine    -   12)        6,8-dichloro-2-methyl-4-(4-piperidin-1-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline;    -   13)        6,8-dichloro-2-methyl-4-(4-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline;    -   14)        6,8-dichloro-2-methyl-4-[4-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-isoquinoline;    -   15)        6,8-dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline;    -   16)        4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;    -   17)        1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-propylurea;    -   18)        1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea;    -   19)        1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;    -   20)        N-[4-(6-methanesulfonyl-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   21)        N-[4-(2,6,8-trimethyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   22)        N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   23)        N-[4-(8-chloro-2-methyl-6-pyrrolidin-1-yl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   24)        N-[4-(8-chloro-2-methyl-6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   25)        N-{4-[8-chloro-2-methyl-6-(4-methyl-piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinolin-4-yl]-phenyl}-acetamide;    -   26)        N-{4-[8-chloro-6-(cyclopropylmethyl-amino)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl]-phenyl}-acetamide;    -   27)        5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoic        acid;    -   28)        5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-N-methyl-benzamide;    -   29)        5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-ethyl-2-hydroxy-benzamide;    -   30)        5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethylamino-ethyl)-2-hydroxy-benzamide;    -   31)        N-[5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoyl]-guanidine;    -   32)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   33)        3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;    -   34)        2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;    -   35)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;    -   36)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;    -   37)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]pentanamide;    -   38)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isobutyramide;    -   39)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2-dimethyl-propionamide;    -   40)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopropanecarboxamide;    -   41)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclobutanecarboxamide;    -   42)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopentanecarboxamide;    -   43)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-acetamide;    -   44)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetylpiperidine-4-carboxamide;    -   45)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-nicotinamide;    -   46)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-sulfonamide;    -   47)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-ethanesulfonamide;    -   48)        N′,N′-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-sulfamide;    -   49)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;    -   50)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;    -   51)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pentanamide;    -   52)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isobutyramide;    -   53)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2-dimethyl-propionamide;    -   54)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopropanecarboxamide;    -   55)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclobutanecarboxamide;    -   56)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopentanecarboxamide;    -   57)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-acetamide;    -   58)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetylpiperidine-4-carboxamide;    -   59)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-nicotinamide;    -   60)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-sulfonamide;    -   61)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-ethanesulfonamide;    -   62)        N′,N′-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-sulfamide;    -   63)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;    -   64)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;    -   65)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-pentanamide;    -   66)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isobutyramide;    -   67)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2-dimethyl-propionamide;    -   68)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopropanecarboxamide;    -   69)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclobutanecarboxamide;    -   70)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopentanecarboxamide;    -   71)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-acetamide;    -   72)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetylpiperidine-4-carboxamide;    -   73)        N-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-sulfonamide;    -   74)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-ethanesulfonamide;    -   75)        N′,N′-dimethylamino-N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-sulfamide;    -   76)        1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;    -   77)        1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea;    -   78)        1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;    -   79)        1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea;    -   80)        N-{5-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide;    -   81)        N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide;    -   82)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,2-dimethyl-1H-imidazole-4-sulfonamide;    -   83)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,2-dimethyl-1H-imidazole-4-sulfonamide;    -   84)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide;    -   85)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide;    -   86)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-5-bromo-thiophene-2-sulfonamide;    -   87)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-5-bromo-thiophene-2-sulfonamide;    -   88)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C-trifluoro-methanesulfonamide;    -   89)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C-trifluoro-methanesulfonamide;    -   90)        4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoroethanesulfonamide;    -   91)        3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-ethanesulfonamide;    -   92)        N-ethyl-N′-4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonylurea;    -   93)        2-chloro-5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide;    -   94) 2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinolin-8-ylamine;    -   95)        6,8-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;    -   96)        4-(8-amino-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenol;    -   97) 8-methoxy-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;    -   98)        2-(8-amino-2-ethyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenol;    -   99)        2-(8-amino-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenol;    -   100)        5-(8-amino-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-methoxy-phenol;    -   101) 2-methyl-8-nitro-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;    -   102)        4-(8-amino-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-1,2-diol;    -   103) 2,8-dimethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;    -   104)        4-(3,4-dichloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline;    -   105)        4-(3,4-dichloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-8-ylamine;    -   106)        4-(2,4-dichloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-8-ylamine;    -   107)        4-(3-chloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-8-ylamine;    -   108) 2,4-dimethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;    -   109) 2-butyl-4-phenyl-1,2,3,4-tetrahydro-isoquinolin-8-ylamine;    -   110)        N-(2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-acetamide;    -   111) 7-chloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;    -   112) 8-chloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;    -   113) 2,6-dimethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;    -   114) 6-chloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;    -   115)        6-methoxy-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;    -   116) 2-ethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;    -   117) 2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;    -   118)        6,8-dichloro-2-ethyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;    -   119)        4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline;    -   120)        2-methyl-4-phenyl-6,8-bis-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline;    -   121)        6,8-dichloro-2-isopropyl-phenyl-1,2,3,4-tetrahydro-isoquinoline;    -   122)        5,8-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;    -   123)        6,8-dichloro-4-(4-fluoro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline;    -   124)        6,8-Dichloro-2-methyl-4-p-tolyl-1,2,3,4-tetrahydro-isoquinoline;    -   125)        5,6-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;    -   126)        6,7-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;    -   127) 8-bromo-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;    -   128)        6,8-dichloro-4-(4-chloro-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline;    -   129)        6,8-dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline;    -   130)        2-Amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   131)        N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-methylamino-acetamide;    -   132)        N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-dimethylamino-acetamide;    -   133)        2-Amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;    -   134)        2-Amino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;    -   135) 2,6-Diamino-hexanoic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   136) Pyrrolidine-2-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   137)        N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isonicotinamide;    -   138) 1H-Pyrrole-3-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   139) 1H-Pyrrole-2-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   140) 1-Methyl-piperidine-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   141) 1,4-Dimethyl-1H-pyrrole-2-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   142) 4-Nitro-1H-pyrrole-2-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   143) 2,5-Dimethyl-1H-pyrrole-3-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   144) 1H-Imidazole-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   145) 1-Methanesulfonyl-piperidine-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   146) 3,5-Dimethyl-1H-pyrazole-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   147) 1H-Pyrazole-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   148) 3-Trifluoromethyl-1H-pyrazole-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   149)        N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-methylamino-acetamide;    -   150)        N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-dimethylamino-acetamide;    -   151)        2-Amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;    -   152)        2-Amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;    -   153) 2,6-Diamino-hexanoic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   154) Pyrrolidine-2-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   155)        N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isonicotinamide;    -   156) 1H-Pyrrole-3-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   157) 1H-Pyrrole-2-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   158) 1-Methyl-piperidine-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   159) 1,4-Dimethyl-1H-pyrrole-2-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   160) 4-Nitro-1H-pyrrole-2-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   161) 2,5-Dimethyl-1H-pyrrole-3-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   162) 1H-Imidazole-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   163) 1-Methanesulfonyl-piperidine-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   164) 3,5-Dimethyl-1H-pyrazole-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   165) 1H-Pyrazole-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   166) 3-Trifluoromethyl-1H-pyrazole-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   167)        1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-thiourea;    -   168)        1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-thiourea;    -   169)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-thiourea;    -   170)        3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-dimethyl-urea;    -   171) 4-Methyl-piperazine-1-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   172) Piperidine-1-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   173) Morpholine-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   174) Pyrrolidine-1-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   175)        3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-diethyl-urea;    -   176)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea;    -   177)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea;    -   178)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(tetrahydro-furan-3-yl)-urea;    -   179)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(tetrahydro-pyran-4-yl)-urea;    -   180)        3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methyl-1-(1-methyl-piperidin-4-yl)-urea;    -   181)        3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-(3-dimethylamino-propyl)-1-methyl-urea;    -   182)        3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-(2-dimethylamino-ethyl)-1-methyl-urea;    -   183)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(3-dimethylamino-propyl)-urea;    -   184)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-methoxy-ethyl)-urea;    -   185)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin-3-yl-urea;    -   186)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin-4-yl-urea;    -   187) 4-Methyl-piperazine-1-carboxylic acid        [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   188)        1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea;    -   189)        3-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-dimethyl-urea;    -   190)        3-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-diethyl-urea;    -   191) Piperidine-1-carboxylic acid        [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   192) Morpholine-4-carboxylic acid        [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   193) Pyrrolidine-1-carboxylic acid        [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   194)        1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea;    -   195) 4-Methyl-piperazine-1-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   196) Pyrrolidine-1-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   197)        1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea;    -   198)        3-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-dimethyl-urea;    -   199)        3-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-diethyl-urea;    -   200)        1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea;    -   201) Piperidine-1-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   202) Morpholine-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   203)        N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-formamide;    -   204)        [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine;    -   205)        1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3-dimethyl-urea;    -   206) 4-Methyl-piperazine-1-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide;    -   207)        1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3-trimethyl-urea;    -   208) Piperidine-1-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide;    -   209) Morpholine-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide;    -   210) Pyrrolidine-1-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide;    -   211)        1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-1-methyl-urea;    -   212)1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,3-diethyl-1-methyl-urea;    -   213)        N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-formamide;    -   214)        [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine;    -   215) Pyrrolidine-1-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide;    -   216) Piperidine-1-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide;    -   217)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3-trimethyl-urea;    -   218)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3-dimethyl-urea;    -   219) Morpholine-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide;    -   220) 4-Methyl-piperazine-1-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide;    -   221)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-1-methyl-urea;    -   222)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3,3-diethyl-1-methyl-urea;    -   223)        [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid 2-dimethylamino-ethyl ester;    -   224)        [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid 2-dimethylamino-ethyl ester;    -   225)        [2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid 2-dimethylamino-ethyl ester;    -   226)        [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid methyl ester;    -   227)        [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid ethyl ester;    -   228)        [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid isopropyl ester;    -   229)        [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid 2,2-dimethyl-propyl ester;    -   230)        [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid methyl ester;    -   231)        [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid isopropyl ester;    -   232)        [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid 2,2-dimethyl-propyl ester;    -   233)        [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid ethyl ester;    -   234)        (+)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide;    -   235)        (−)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide;    -   236)        (+)-1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;    -   237)        (−)-1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;    -   238)        N-[3-(6,8-Difluoro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   239)        4-(3-Bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline;    -   240)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-hydroxy-ethyl)-urea;    -   241)        3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic        acid ethyl ester; and    -   242)        3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic        acid;        and the pharmaceutically acceptable salts thereof.

In one embodiment, the invention encompasses the use of the compounds ofthe formula I for the treatment of disorders which can be influenced byinhibition of the sodium-proton exchange of subtype III (NHE3), chosenfrom:

-   -   1)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   2)        4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide;    -   3)        3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide;    -   4)        4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic        acid;    -   5)        4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-ethyl-benzamide;    -   6)        4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-propyl-benzamide;    -   7)        4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethylamino-ethyl)-benzamide;    -   8)        6,8-dichloro-2-methyl-4-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline;    -   9)        4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;    -   10)        1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea;    -   11)        1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;    -   12)        N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   13)        5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoic        acid;    -   14)        5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethylamino-ethyl)-2-hydroxy-benzamide;    -   15)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;    -   16)        3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;    -   17)        2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;    -   18)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;    -   19)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetyl-piperidine-4-carboxamide;    -   20)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-sulfonamide;    -   21)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-ethanesulfonamide;    -   22)        N′,N′-dimethylamino-N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-sulfamide;    -   23)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;    -   24)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;    -   25)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-isobutyramide;    -   26)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopropanecarboxamide;    -   27)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclobutanecarboxamide;    -   28)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2,2,2-trifluoro-acetamide;    -   29)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetyl-piperidine-4-carboxamide;    -   30)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-nicotinamide;    -   31)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methane-sulfonamide;    -   32)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-ethanesulfonamide;    -   33)        N′,N′-dimethylamino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-sulfamide;    -   34)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-cyclopropanecarboxamide;    -   35)        N-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-acetyl-piperidine-4-carboxamide;    -   36)        1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;    -   37)        1-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea;    -   38)        1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;    -   39)        1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea;    -   40)        N-{5-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide;    -   41)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,2-dimethyl-1H-imidazole-4-sulfonamide;    -   42)        N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C-trifluoro-methanesulfonamide;    -   43)        N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-C,C,C-trifluoro-methanesulfonamide;    -   44)        N-ethyl-N′-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonylurea;    -   45)        N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-dimethylamino-acetamide;    -   46) 2,6-Diamino-hexanoic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   47) 1H-Pyrrole-3-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   48) 1-Methyl-piperidine-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   49) 1-Methanesulfonyl-piperidine-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   50) 1H-Pyrazole-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   51)        N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-methylamino-acetamide;    -   52)        N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-2-dimethylamino-acetamide;    -   53)        2-Amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-propionamide;    -   54)        2-Amino-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-butyramide;    -   55) 2,6-Diamino-hexanoic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   56) 1-Methyl-piperidine-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   57) 1H-Imidazole-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   58) 1-Methanesulfonyl-piperidine-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   59) 3,5-Dimethyl-1H-pyrazole-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   60) 1H-Pyrazole-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   61)        3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-dimethyl-urea;    -   62) 4-Methyl-piperazine-1-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   63) Piperidine-1-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   64) Morpholine-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   65) Pyrrolidine-1-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   66)        3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-diethyl-urea;    -   67)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea;    -   68)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea;    -   69)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(tetrahydro-furan-3-yl)-urea;    -   70)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(tetrahydro-pyran-4-yl)-urea;    -   71)        3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-methyl-1-(1-methyl-piperidin-4-yl)-urea;    -   72)        3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-(3-dimethylamino-propyl)-1-methyl-urea;    -   73)        3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1-(2-dimethylamino-ethyl)-1-methyl-urea;    -   74)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(3-dimethylamino-propyl)-urea;    -   75)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-methoxy-ethyl)-urea;    -   76)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin-3-yl-urea;    -   77)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-pyridin-4-yl-urea;    -   78) 4-Methyl-piperazine-1-carboxylic acid        [2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   79)        1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea;    -   80)        1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea;    -   81) 4-Methyl-piperazine-1-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   82)        1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-urea;    -   83)        3-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-dimethyl-urea;    -   84)        3-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-diethyl-urea;    -   85)        1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-urea;    -   86) Morpholine-4-carboxylic acid        [4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide;    -   87)        N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-formamide;    -   88)        [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine;    -   89)        N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-formamide;    -   90)        [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine;    -   91)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3,3-trimethyl-urea;    -   92)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3-dimethyl-urea;    -   93) Morpholine-4-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide;    -   94) 4-Methyl-piperazine-1-carboxylic acid        [3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amide;    -   95)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-dimethylamino-ethyl)-1-methyl-urea;    -   96)        [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid 2-dimethylamino-ethyl ester;    -   97)        [4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid 2-dimethylamino-ethyl ester;    -   98)        [2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid 2-dimethylamino-ethyl ester;    -   99)        [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic        acid methyl ester;    -   100) (R or        S)—N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide;    -   101) (R or        S)-1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea;    -   102)        1-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-(2-hydroxy-ethyl)-urea;    -   103)        3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic        acid ethyl-ester; and    -   104)        3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoic        acid        and the pharmaceutically acceptable salts thereof.

If the compounds of the formula I contain one or more centers ofasymmetry, these may have both the S and the R configuration. Thecompounds may be in the form of optical isomers, of diastereomers, ofracemates or of mixtures thereof.

The defined alkyl radicals and partly or completely fluorinated alkylradicals may be both straight-chain and branched. Groups C_(a)H_(2a-1)and their analogs as far as C_(yy)H_(2yy-1) mean either thecorresponding alkenyls, cycloalkyls, cycloalkylalkyls oralkylcycloalkyls.

Appropriate heteroaryls are, for example, 2- or 3-thienyl, 2- or3-furyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or5-pyrazolyl, 1,2,3-triazol-1-, -4- or 5-yl, 1,2,4-triazol-1-, -3- or-5-yl, 1- or 5-tetrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl,1,2,3-oxadiazol-4- or 5-yl, 1,2,4-oxadiazol-3-or 5-yl,1,3,4-oxadiazol-2-yl or -5-yl, 2-, 4- or 5-thiazolyl, 3-, 4- or5-isothiazolyl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or-5-yl, 1,2,3-thiadiazol-4- or 5-yl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or6-pyrimidinyl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-,7- or 8-isoquinolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-,6-, 7- or 8-cinnolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 1-, 4-,5-, 6-, 7- or 8-phthalazinyl. The corresponding N-oxides of thesecompounds are additionally encompassed, that is to say, for example,1-oxy-2-, 3- or 4-pyridyl.

In one embodiment, the 5- or 6-membered heterocycles are chosen. In afurther embodiment, imidazolyl, pyrazolyl, pyrrolyl, triazolyl,tetrazolyl, thiazolyl and oxazolyl are chosen.

The terminal CH₃ groups in an alkyl chain are also regarded as CH₂ unitsand are in this connection viewed as CH₂ groups.

Methods for preparing the compounds of the invention are also described.

The substances described herein can be prepared, for example, startingfrom the benzylamine precursors IV. These in turn can, if not obtainablecommercially, be synthesized by standard processes from thecorresponding benzyl chlorides or bromides III.

The benzylamines IV obtained in this way may be alkylated in a mannerknown to the skilled worker with the appropriately substitutedalpha-bromoacetophenone compounds V.

The alpha-bromacetophenone compounds V may be obtained from thecorresponding acetophenone precursors by bromination in processes knownfrom the literature. The desired tetrahydroisoquinolines I may beobtained by known processes by reduction of the carbonyl group in VI andsubsequent acid-catalyzed cyclization of the corresponding alcohols VII(cf. Tetrahedron Lett.; 1989, 30, 5837; Org. Prep. Proced. Int.; 1995,27, 513).

When R6 is not equal to H, the desired compounds of the formula I may beprepared for example from the iodides VIII by halogen/metal exchange andsubsequent nucleophilic attack of the intermediate organolithium specieson the carbonyl group (cf. Chem. Pharm. Bull.; 1995, 43,1543).

The tertiary alcohols synthesized in this way may be converted by knownmethods into other derivatives.

Alkyl-branched analogs (i) may be prepared by alkylating thecorresponding diphenylacetic esters X in the alpha position by knownmethods. The desired product XI may be converted by standard processesinto the corresponding amides XII, which may be converted into thedesired tetrahydroisoquinolines I in a Pictet-Spengler-analogousreaction (cf. Tetrahedron; 1987, 43, 439; Chem. Pharm. Bull.; 1985, 33,340).

As used herein, treating or treatment includes the treating of, forexample, a patient inflicted with a disease or condition, as well as theprevention, prophylaxis, or protective treatment of a patient. Treatmentalso includes treating a subject susceptible to or predisposed todeveloping a disease or condition, which could include patients in whoma disease or condition has not yet presented as well as patients in whomthe disease has been successfully treated but could redevelop orreoccur.

In one embodiment, the compounds of the formula I may be excellentinhibitors of the sodium-hydrogen exchanger (NHE)—especially of thesodium of the sodium-hydrogen exchanger of subtype 3 (NHE3).

On the basis of these properties, the compounds may be suitable for thetreatment of disorders caused by oxygen deficiency. The compounds maybe, as a result of their pharmacological properties, suitable asantiarrhythmic medicaments with a cardioprotective component forprophylaxis of infarction and for treatment of infarction, and for thetreatment of angina pectoris, in which connection they may also inhibitor reduce in a preventive manner the pathophysiological processesassociated with the development of ischemia-induced damage, inparticular in the induction of ischemia-induced cardiac arrhythmias.Because of their possible protective effects against pathologicalhypoxic and ischemic situations, the compounds of the formula I whichare used according to the invention may, as a result of inhibition ofthe cellular Na⁺/H⁺ exchange mechanism, be used as medicaments for thetreatment of all acute or chronic damage induced by ischemia ordisorders induced primarily or secondarily thereby. This relates to thepossible use thereof as medicaments for surgical interventions, e.g. inorgan transplantations, in which cases the compounds may be used, forexmple, both to protect the organs in the donor before and duringremoval, to protect removed organs for example on treatment with orstorage thereof in physiological bath fluids, as well as during thetransfer into the recipient organism. The compounds may in someembodiments likewise be valuable medicaments with a protective actionduring the performance of angioplastic surgical interventions, forexample on the heart as well as peripheral vessels. In accordance withtheir possible protective action against ischemia-induced damage, thecompounds may also be suitable as medicaments for the treatment ofischemias of the nervous system, especially of the CNS, in whichconnection they may be suitable for example for the treatment of strokeor of cerebral edema. In addition, the compounds of the formula I whichare used according to the invention may likewise be suitable for thetreatment of types of shock, such as, for example, of allergic,cardiogenic, hypovolemic and bacterial shock.

In addition, the compounds may induce an improvement in the respiratorydrive and may therefore be used to treat respiratory conditionsassociated with the following clinical conditions and diseases:disturbance of central respiratory drive (e.g. central sleep apnea,sudden infant death, postoperative hypoxia), muscle-related breathingdisorders, breathing disorders after long-term ventilation, breathingdisorders associated with altitude adaptation, obstructive and mixedtype of sleep apnea, acute and chronic pulmonary disorders with hypoxiaand hypercapnia.

The compounds additionally may in some embodiments increase the tone ofthe muscles of the upper airways, so that snoring is suppressed.

A combination of an NHE inhibitor with a carbonic anhydrase inhibitor(e.g. acetazolamide), the latter inducing metabolic acidosis and thusitself increasing respiratory activity, may in some embodiments prove tobe advantageous due to an enhanced effect and reduced use of activeingredient.

In one embodiment, the compounds used according to the invention have amild laxative effect and accordingly may be used advantageously aslaxatives or if there is a risk of constipation, in which case thecompounds may prevent the ischemic damage associated with constipationin the intestinal region.

In another embodiment, it is possible to prevent the formation of gallstones.

In one embodiment, the compounds of the formula I used according to theinvention may demonstrate a strong inhibitory effect on theproliferation of cells, for example of fibroblast cell proliferation andthe proliferation of smooth muscular muscle cells. The compounds of theformula I may therefore is some embodiments be suitable as valuabletherapeutic agents for diseases in which cell proliferation represents aprimary or secondary cause, and may therefore be used asantiatherosclerotic agents, agents to prevent late complications ofdiabetes, cancers, fibrotic disorders such as pulmonary fibrosis,hepatic fibrosis or renal fibrosis, organ hypertrophies andhyperplasias, in particular for prostate hyperplasia or prostatehypertrophy.

In another embodiment, the compounds used according to the invention maybe effective inhibitors of the cellular sodium-proton antiporter (Na/Hexchanger) which is elevated in numerous disorders (essentialhypertension, atherosclerosis, diabetes, etc.), also in those cellswhich are readily amenable to measurements, such as, for example, inerythrocytes, platelets or leukocytes. The compounds used according tothe invention in some embodiments therefore may be suitable as excellentand simple scientific tools, for example in their use as diagnosticagents for determining and distinguishing different types ofhypertension, but also of atherosclerosis, of diabetes, proliferativedisorders etc. The compounds of the formula I may also be suitable forpreventive therapy to prevent the development of high blood pressure,for example of essential hypertension.

In one embodiment, it has additionally been found that NHE inhibitorsmay show a beneficial effect on serum lipoproteins. It is generallyacknowledged that blood lipid levels which are too high, so-calledhyperlipoproteinemias, represent a considerable risk factor for thedevelopment of arteriosclerotic vascular lesions, especially coronaryheart disease. The reduction of elevated serum lipoproteins thereforemay have exceptional importance for the prophylaxis and regression ofatherosclerotic lesions. The compounds used according to the inventionmay therefore in some embodiments be used for the prophylaxis andregression of atherosclerotic lesions by eliminating a causal riskfactor. With this protection of the vessels against the syndrome ofendothelial dysfunction, compounds of the formula I may be valuablemedicaments for the prevention and treatment of coronary vasospasms, ofatherogenesis and of atherosclerosis, of left-ventricular hypertrophyand of dilated cardiomyopathy, and thrombotic disorders.

In certain embodiment the compounds of the invention may therefore beused for producing a medicament for the prevention and treatment ofsleep apneas and muscle-related respiratory disorders; for producing amedicament for the prevention and treatment of snoring; for producing amedicament for lowering blood pressure; for producing a medicament forthe prevention and treatment of disorders induced by ischemia andreperfusion of central and peripheral organs, such as acute renalfailure, stroke, endogenous states of shock, intestinal disorders etc.;for producing a medicament for the treatment of late damage fromdiabetes and chronic renal disorders, in particular of all inflammationsof the kidneys (nephritides) which are associated with increasedprotein/albumin excretion; for producing a medicament for the treatmentof infection by ectoparasites in human and veterinary medicine; forproducing a medicament for the treatment of said disorders incombinations with hypotensive substances, preferably with angiotensinconverting enzyme (ACE) inhibitors, with diuretics and saluretics suchas furosemide, hydrochlorothiazide, pseudoaldosterone antagonists andaldosterone antagonists; with adenosine receptor modulators, inparticular with adenosine receptor activators (A2 agonists); and withangiotensin receptor antagonists.

In another embodiment, at least one sodium-proton exchange inhibitors ofthe formula I is administered as a medicament for lowering elevatedblood lipid levels, including as the combination of sodium-protonexchange inhibitors with hypotensive medicaments and/or medicaments withhypolipidemic activity.

Medicaments which comprise a compound of the invention can in thisconnection may be administered orally, parenterally, intravenously,rectally, transdermally or by inhalation, the preferred administrationbeing dependent on the particular characteristics of the disorder. Thecompounds of the invention may moreover may be used alone or togetherwith pharmaceutical excipients, both in veterinary medicine and in humanmedicine.

The excipients suitable for the desired pharmaceutical formulation arefamiliar to the skilled worker on the basis of his expert knowledge.Besides solvents, gel formers, suppository bases, tablet excipients, andother active ingredient carriers, it is possible to use, for example,antioxidants, dispersants, emulsifiers, antifoams, flavorings,preservatives, solubilizers or colors.

For a form for oral administration, the active compounds may be mixedwith additives suitable for this purpose, such as carriers, stabilizersor inert diluents, and converted by conventional methods into suitabledosage forms such as tablets, coated tablets, hard gelatin capsules,aqueous, alcoholic or oily solutions. Examples of inert carriers whichcan be used include, for example, gum arabic, magnesia, magnesiumcarbonate, potassium phosphate, lactose, glucose or starch, especiallycorn starch. It is moreover possible for the preparation to take placeboth as dry granules and as wet granules. Examples of suitable oilycarriers or solvents are vegetable or animal oils such as sunflower oilor fish liver oil.

For subcutaneous or intravenous administration, the active compoundsused may be converted, if desired with the substances customary for thispurpose, such as solubilizers, emulsifiers or other excipients, into asolution, suspension or emulsion. Examples of suitable solvents are:water, physiological saline or alcohols, e.g. ethanol, propanol,glycerol, as well as sugar solutions such as glucose or mannitolsolutions, or else a mixture of the various solvents mentioned.

Compounds of the invention are also suitable as a pharmaceuticalformulation for administration in the form of aerosols or sprays are,for example, solutions, suspensions or emulsions of the activeingredient of the formula I in a pharmaceutically acceptable solventsuch as, in particular, ethanol or water, or a mixture of such solvents.

The formulation may, if required, also contain other pharmaceuticalexcipients such as surfactants, emulsifiers and stabilizers, and apropellant gas. Such a preparation normally contains the activeingredient in a concentration of about 0.1 to 10, in particular of about0.3 to 3, % by weight.

The dosage of the active ingredient of the coumpounds of the inventionto be administered, and the frequency of administration, depend on thepotency and duration of action of the compounds used; additionally alsoon the nature and severity of the disorder to be treated and on the sex,age, weight and individual responsiveness of the mammal to be treated.

On average, the daily dose of a compound of the formula I for a patientweighing about 75 kg is at least 0.001 mg/kg, preferably 0.001 mg/kg, toa maximum of 10 mg/kg, preferably 1 mg/kg, of body weight. For acuteepisodes of the disorder, for example immediately after suffering amyocardial infarction, higher and, in particular, more frequent dosagesmay also be necessary, e.g. up to 4 single doses a day. Up to 200 mg aday may be necessary, in particular on i.v. administration, for examplefor a patient with infarction in the intensive care unit.

DESCRIPTIONS OF EXPERIMENTS AND EXAMPLES

List of Abbreviations Used: R_(t) retention time TFA trifluoroaceticacid HPLC high performance liquid chromatography eq equivalent LCMSliquid chromatography mass spectroscopy MS mass spectroscopy CI chemicalionization RT room temperature THF tetrahydrofuran TOTUO-[(ethoxycarbonyl)-cyanomethyleneamino]-N,N,N′,N′- tetramethyluroniumtetrafluoroborate DMSO dimethyl sulfoxide abs. absolute decomp.decomposition DMF dimethylformamidGeneral:

The retention times (R_(t)) indicated below relate to LCMS measurementswith the following parameters: Method A: stationary phase: MerckPurospher 3μ 2 × 55 mm mobile phase: 95% H₂O (0.05% TFA) → 95%acetonitrile; 4 min; 95% acetonitrile; 1.5 min → 5% acetonitrile; 1 min;0.5 ml/min, 30° C. Method B: stationary phase: Merck Purospher 3μ 2 × 55mm mobile Phase: 0 min 90% H₂O (0.05% TFA) 2.5 min-95% acetoni- trile;95% acetonitrile to 3.3 min; 10% acetonitrile 3.4 min; 1 ml/min. MethodB1: stationary phase: YMC, J'sphere ODS H80 4μ 2 × 20 mm mobile phase: 0min 90% H₂O (0.05% TFA) 1,9 min-95% acetoni- trile; 95% acetonitrile bis2,4 min; 10% acetonitrile 2,45 min; 1 ml/min. Method C: stationaryphase: Merck LiChroCart 55-2 Purospher STAR RP 18e solvent: solvent A:acetonitrile/water 90:10 + 0.5% HCOOH solvent B: acetonitrile/water10:90 + 0.5% HCOOH flow rate: 0.75 ml/min time[min] solvent B[%] 0.0095.0 0.50 95.0 1.75 5.0 4.25 5.0 4.50 95.0 5.00 95.0 stop time: 6.20 mintemperature: 40° C. Method D: stationary phase: Merck RP18 PurospherStar, 55 × 2 mm, 3μ KorngröBe solvent: Solvent A: acetonitrile + 0.08%HCOOH Solvent B: water + 0.1% HCOOH Flow rate 0.45 ml/min time [min]solvent B[%] 0 95 5 5 7 5 8 95 9 5 temperature: room temperature

Example 1N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide

Intermediate 1: 2,4-Dichlorobenzyl-(methyl)-amine was prepared bymethods known from the literature (J. Med. Chem.; 1984, 27, 1111).

Intermediate 2: N-[4-(2-Bromo-acetyl)-phenyl]-acetamide wais synthesizedin a manner known to the skilled worker by bromination ofN-(4-acetyl-phenyl)-acetamide.

The starting compound (0.256 mol) was introduced into 300 ml of aceticacid and, at 60° C, a solution of 39.9 g of bromine (1.0 eq) in 60 ml ofacetic acid was added dropwise. After 1.5 h, the reaction mixture wasallowed to cool to room temperature and was added to 1 l of ice-water.The precipitate was filtered off with suction, washed with water anddried, with 60 g of the title compound being isolated (melting point:192° C.).

Intermediate 3:N-{4-[2-(2,4-Dichloro-benzylamino)-acetyl]-phenyl}-acetamide; 37.1 g(0.195 mol) of intermediate 1 was introduced into 400 ml of dioxane, anda solution of 60 g (0.234 mol) of intermediate 2 in 600 ml of dioxanewas added. 134 ml of triethylamine were added, and the mixture wasstirred at room temperature for 4 h. After standing overnight, theprecipitate was filtered off and the filtrate was concentrated in vacuo.The residue was taken up in ethyl acetate, washed with NaHCO₃ and H₂O,dried with MgSO₄ and concentrated. The oily residue resulting therebywas triturated with an ethyl acetate/ether mixture, resulting in 36 g ofintermediate 3 in the form of a crystalline solid (melting point:115-117° C.).

Intermediate 4:

N-{4-[2-(2,4-Dichloro-benzylamino)-1-hydroxy-ethyl]-phenyl}-acetamide;36 g (0.099 mol) of intermediate 3 was dissolved in 500 ml of methanoland, at 0° C., 7.8 g (2 eq) of sodium borohydride was added. The mixturewas then stirred at 0° C. for 30 min and at room temperature for afurther hour. For workup, the reaction mixture was concentrated and theresidue was partitioned between 1 N HCl and ethyl acetate. The aqueousphase was separated off, adjusted to pH 9 and extracted twice with ethylacetate. The combined organic phases were dried with MgSO₄ andconcentrated. The crude product obtained in this way was reacted furtherwithout further purification.

N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;20 g (0.054 mol) of intermediate 4 was dissolved in 250 ml ofdichloromethane and, at 0° C., 250 ml of conc. H₂SO₄ was added dropwise.The mixture was stirred at 0° C. for 2 h and at room temperature for 1h. For workup, the reaction mixture was added to ice-water, and theprecipitate was filtered off with suction. The precipitate was taken upin 300 ml of 1 N NaOH and extracted three times with ethyl acetate.Drying of the organic phases and concentration affords a crude productwhich was triturated with diisopropyl ether, whereupon 11.7 g of thecompound of the example were isolated as a crystalline solid (meltingpoint: 205-206° C.)

1a:N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide-hydrochloride;

An analytical sample (100 mg) of the title compound from example 1 wassuspended in 10 ml of 2 N HCl, and THF was added until a clear solutionwas produced. It was concentrated in vacuo, and the residue wastriturated with ether and filtered off with suction, whereupon the titlecompound was obtained as a crystalline solid (R_(t)=3.807 min (methodA); melting point.: 125° C. with decomposition).

Example 2

2a:(+)-4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-sulfonamidehydrochloride;

2b:(+)-3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-sulfonamidehydrochloride;

2c:(−)-4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-sulfonamideacetate;

2d:(−)-3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-sulfonamideacetate;

Intermediate 1: 2,4-Dichlorobenzyl-(methyl)-amine was prepared bymethods known from the literature (J. Med. Chem.; 1984, 27,1111).

Intermediate 2:2-[(2,4-Dichloro-benzyl)-methyl-amino]-1-phenyl-ethanone; Intermediate 1was reacted with 2-bromo-1-phenyl-ethanone in the manner described inexample 1, intermediate 3. Workup in an analogous manner andpurification on silica gel affords the desired alkylation product ingood yield as a yellowish oil (R_(t)=4.188 min (method A);MS(Cl⁺)=308.2/310.2).

Intermediate 3: 2-[(2,4-Dichloro-benzyl)-methyl-amino]-1-phenyl-ethanol;Intermediate 2 was reduced with sodium borohydride in the mannerdescribed in example 1, intermediate 4. Once monitoring of the reactionindicates complete conversion, the mixture was concentrated and theresidue was taken up in ethyl acetate. It was washed twice with H₂O,dried with MgSO₄ and freed of solvent. The crude product, which wasobtained in quantitative yield, was reacted further without furtherpurification (R_(t)=4.149 min (method A); MS(Cl⁺)=310.2/312.2).

Intermediate 4:6,8-Dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline; 20 g(64.5 mmol) of intermediate 3 were dissolved in 55 ml of dichloromethaneand cooled to 0° C. This solution was added dropwise to 55 ml ofprecooled conc. H₂SO₄ and then stirred at room temperature for twohours. For workup, the mixture was poured onto ice and made stronglyalkaline with 6 N NaOH. Three extractions with dichloromethane werecarried out. The combined organic phases were dried with MgSO₄ andconcentrated. The oily crude product was purified on silica gel,resulting in intermediate 4 in a yield of 53% (R_(t)=4.444 min (methodA); MS(Cl⁺)=292.2/294.2).

4a: (−)-6,8-Dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinolinetrifluoroacetate;

4b: (+)-6,8-Dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinolinetrifluoroacetate;

Intermediate 4 was separated into the two enantiomers by HPLC on achiral phase.

-   -   chiral column: Chiralpak OD 250×4.6 cm;    -   solvent: n-heptane/isopropanol 7:3+0.1% TFA;    -   flow rate: 1 ml/min;    -   R_(t)((−)-enantiomer/4a)=9.340 min;    -   R_(t)((+)-enantiomer/4b)=20.327 min.

2a:(+)-4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-sulfonamidehydrochloride;

2b:(+)-3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-sulfonamidehydrochloride;

A suspension of 500 mg (1.7 mmol) of intermediate 4a in 10 ml ofdichloromethane was introduced at 0° C. into 1.2 ml of chlorosulfonicacid. The mixture was stirred at 0° C. for one hour and at roomtemperature for a further hour. A further 5 ml of chlorosulfonic acidwas added and the mixture was stirred at room temperature for one hour.For workup, it was poured onto ice and adjusted to pH 8 with NaHCO₃.Three extractions with ethyl acetate were carried out. The combinedorganic phases were dried with Na₂SO₄ and freed of solvent. The crudeproduct obtained in this way was heated in 20 ml of conc. NH₃ solutionat 90° C. for three hours. After the conversion was complete, thereaction solution was concentrated and the residue was partitionedbetween H₂O and ethyl acetate. The organic phase was separated off andthe aqueous phase was extracted once more with ethyl acetate. Thecombined organic phases were dried with Na₂SO₄ and the solvent wasremoved in vacuo. Subsequent chromatography on silica gel affords 335 mgof a mixture of example 2a and 2b in the form of a yellow amorphoussolid. Further purification on a preparative HPLC affords 212 mg of thepara-substituted title compound 2a, plus 58 mg of the meta isomer 2b.

Conditions for the preparative HPLC.

-   -   chiral column: Chiralpak AS 250×4.6 mm;    -   solvents: n-heptane/ethanol/methanol/acetonitrile 20:1.5:0.5:0.5    -   flow rate: 1 ml/min;    -   R_(t)(main fraction)=14.145 min (→2a);    -   R_(t)(subsidiary fraction)=11.623 min (→2b).

Both fractions were dissolved in methanol/2 N HCl mixture and freezedried, and it was possible to obtain the title compounds 2a and 2b inthe form of crystalline solids. (R_(t)(2a)=3.630 min (method A);MS(2a),(ES⁺)=371.3/373.3 (M⁺+H)/412.3/414.3 (M⁺+CH₃CN); R_(t)(2b)=3.668min (method A); MS(2b),(ES⁺)=371.3/373.3 (M⁺+H)/412.3/414.3 (M⁺+CH₃CN).

2c:(−)-4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-sulfonamideacetate;

2d:(−)-3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-sulfonamideacetate;

The title compound was synthesized by the method described under 2a/2b,using intermediate 4b as starting compound. The purification andseparation from the meta isomer which was to be expected and takes placeunder the following conditions: chiral column: Chiralpak AS 250×4.6/12mm;

-   -   solvent: acetonitrile    -   flow rate: 1 ml/min;    -   R_(t)(main fraction)=4.394 min (→2c);    -   R_(t)(subsidiary fraction)=4.130 min (→2d).

The purified products were each taken up in a 10% acetic acid solutionand freeze dried, resulting in the desired acetates as slightlyyellowish solids (R_(t)(2c)=3.656 min (method A); MS(ES⁺)=371.1/373.1(M⁺+H)/412.1/414.1 (M⁺+CH₃CN)); (R_(t)(2d)=1.562 min (method B);MS(ES⁺)=371.1/373.1 (M⁺+H)/412.1/414.1 (M⁺+CH₃CN)).

Example 34-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N,N-dimethyl-benzenesulfonamide,hydrochloride

6,8-Dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline(intermediate 4, example 2) was introduced in portions intochlorosulfonic acid (6.6 ml). The mixture was subsequently stirred at40° C. for one hour. The reaction mixture was then cooled to roomtemperature and an ice/water mixture was added. The precipitate whichseparated out during this was filtered off with suction and taken up inethyl acetate which, after washing with saturated brine was dried overmagnesium sulfate. Subsequent concentration afforded4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonylchloride as a solid crude product, a portion of which (150 mg) wasdirectly introduced in portions into dimethylamine solution (5 ml,approx. 40% in water) cooled to 10° C. The resulting suspension wassubsequently stirred at this temperature for 1.5 h. Then ice-water wasadded and, after extraction three times with ethyl acetate, the combinedethyl acetate phases were washed with saturated brine and dried overmagnesium sulfate. The residue was taken up with water and, afteraddition of 2 N HCl, freeze dried. The crude product obtained in thisway was then purified by preparative HPLC.

Conditions:

stationary phase: Merck Purospher RP18 (10 μM) 250×25 mm

mobile phase: 90% H₂O (0.05% TFA)→90% acetonitrile; 40 min; flow rate:25 m/min

The fractions containing the product were combined, the acetonitrile wasstripped off in a rotary evaporator, and the aqueous phase was washedwith saturated potassium carbonate solution and then extracted threetimes with ethyl acetate. The combined ethyl acetate phases were washedwith saturated brine, dried over magnesium sulfate and concentrated. Theresidue was taken up in water and, after addition of 2 N HCl, freezedried. 80 mg of a pale solid were obtained. This consisted of ˜80% ofthe desired compound, in addition to ˜20% of a regioisomer (R_(t)=4.000min (method A); MS(Cl⁺)=399.1).

Example 4

4a:4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide,hydrochloride;

Intermediate 1:4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-benzenesulfonylchloride

At 0° C., 1 mmol of6,8-dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline(intermediate 4, example 2) was introduced into 1 ml of chlorosulfonicacid and stirred at room temperature for 3 hours. For workup, thereaction mixture was poured onto ice, adjusted to pH 7 to 8 with 1 NNaOH and extracted twice with ethyl acetate. The combined ethyl acetatephases were dried with Na₂SO₄ and concentrated in a rotary evaporator.The crude product obtained in this way was reacted further withoutfurther purification.

Intermediate 2:4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide

319 mg of intermediate 1 were suspended in 6 ml of 25% strength ammoniaand heated to 90° C. After 3 h, the mixture was diluted with H₂O andextracted with ethyl acetate. The organic phase was separated off anddried with Na₂SO₄, resulting in 165 mg of the title compound.

4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide,hydrochloride;

145 mg of intermediate 2 were suspended in 15 ml of diethyl ether, and 1ml of ethereal HCl was added. After stirring at room temperature for 30minutes, the precipitate was filtered off with suction and dried,resulting in 136 mg of the hydrochloride in the form of a yellowishsolid.

4b:4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonamide,acetate;

255 mg of intermediate 2, example 8, was mixed with 5 ml of glacialacetic acid, and 50 ml of H₂O was added. Filtration of sparingly solubleconstituents was followed by freeze drying, resulting in 250 mg of thetitle compound.

Example 54-(4-Bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline,hydrochloride

Intermediate 1:1-(4-Bromo-phenyl)-2-[(2,4-dichloro-benzyl)-methyl-amino]-ethanone;(2,4-Dichloro-benzyl)-methyl-amine (see example 1, intermediate 1) and2-bromo-1-(4-bromo-phenyl)-ethanone was reacted in analogy to the methoddescribed in example 1, intermediate 3. After analogous workup andchromatography on silica gel, the alkylation product was isolated in ayield of 69%.

Intermediate 2:1-(4-Bromo-phenyl)-2-[(2,4-dichloro-benzyl)-methyl-amino]-ethanol;Intermediate 1 was reduced to the corresponding alcohol with 2equivalents of NaBH₄ in analogy to the manner described for intermediate4, example 1, and the alcohol was isolated in a yield of 86%.

Intermediate 3:4-(4-Bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline;

5.45 g (14.0 mmol) of1-(4-bromo-phenyl)-2-[(2,4-dichloro-benzyl)-methyl-amino]-ethanol wasintroduced into 15 ml of dichloromethane and, at 0° C., 15 ml of conc.H₂SO₄ are added. After stirring at room temperature for 2 hours, thereaction mixture was poured onto ice and made alkaline with 6 N NaOH.Three extractions with dichloromethane were carried out. The combinedorganic phases were dried with MgSO₄ and concentrated. For furtherpurification, the residue was chromatographed on silica gel, resultingin 2.6 g of the title compound as a yellowish oil.

4-(4-Bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline,hydrochloride;

300 mg of4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolinewas stirred in 2 N HCl at room temperature. The resulting precipitatewas filtered off with suction and dried.

Example 64-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoicacid

4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoicacid; 5.57 g (15 mmol) of4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline(example 5, intermediate 3) was dissolved in 150 ml of abs. DMF/benzene(1:1). After the solution was degassed, under argon 1.18 g (4.5 mmol) oftriphenylphosphine and 1.17 g (9 mmol) of Ca(HCO₂)₂ were added. Afterrenewed flushing with argon, 867 mg (0.75 mmol) of Pd(PPh₃)₄ was addedand carbon monoxide was passed into the solution. The mixture wasstirred at 120° C. After six hours at 120° C. and standing overnightunder argon, a further 867 mg (0.75 mmol) of Pd(PPh₃)₄ was added andstirring at 120° C. and passing carbon monoxide into the solution wascontinued for eight hours. After again standing overnight, 135 mg ofPdCl₂ was added and reaction was allowed to take place under the sameconditions. For workup, the solvent was removed in vacuo and the residuewas taken up in ethyl acetate. Three extractions with 2 N NaOH werecarried out. The combined aqueous phases were adjusted to pH 6 with 6 NHCl and extracted three times with ethyl acetate. The organic phaseswere dried with MgSO₄ and freed of solvent. The residue was purified onsilica gel using a dichloromethane/methanol mixture, resulting in 420 mgof the title compound (R_(t)=4.025 min (method A); MS(Cl⁺)=336.1/338.1).

Example 74-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-ethyl-benzamide,trifluoroacetate

146 mg (0.43 mmol) of4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoicacid (see example 6) was dissolved in 5 ml of DMF, and 1.0 equivalent oftriethylamine was added. At 0° C., a solution of 141 mg (0.43 mmol) TOTUin 3 ml of DMF was added. The mixture was stirred at 0° C. for 30 minand at room temperature for 30 min. This solution was then added at 0°C. to a solution of 0.28 ml of 2 M ethylamine solution and 0.06 ml(0.043 mmol) of triethylamine in 5 ml of DMF, and the reaction mixturewas stirred at room temperature for three hours. For workup, the solventwas distilled off in vacuo, and the residue was taken up in ethylacetate and washed twice with 1 N KOH and once with H₂O. The organicphase was dried with Na₂SO₄ and concentrated. Chromatography on silicagel (dichloromethane/methanol 95:5) was used for further purification.Further purification on a preparative HPLC(acetonitrile/H₂O/trifluoroacetic acid) afforded the desired carboxamideas trifluoroacetate (R_(t)=4.169 min (method A); MS(Cl⁺)=363.3/365.3).

Example 84-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-propyl-benzamide,trifluoroacetate

The title compound was prepared by the method described in example 7starting from n-propylamine and4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzoicacid (see example 6).

(R_(t)=1.881 min (method B); MS(Cl⁺)=377.3/379.3).

Example 94-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethylamino-ethyl)-benzamide,trifluoroacetate

was prepared in analogy to example 7 starting from example 6 andN1,N1-dimethylethane-1,2-diamine by a TOTU-mediated coupling reaction(R_(t)=1.449 min (method B); MS(Cl⁺)=406.3/408.3).

Example 106,8-Dichloro-2-methyl-4-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline,trifluoroacetate

456 mg (1.4 mmol) of Cs₂CO₃, 6.75 mg (0.03 mmol) of palladium acetateand 28 mg (0.045 mmol) of 2,2-bis-(diphenylphosphino)-1,1-binaphthyl wasintroduced into 5 ml of abs. toluene. Under argon, a solution of 0.104ml (1.2 mmol) of morpholine in 2.5 ml of abs. DMF, and a solution of 371mg (1.0 mmol) of4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolinein 2.5 ml of abs. toluene was added, and the mixture was stirred at 100°C. for a total of 9 hours. For workup, the solvent was removed, theresidue was taken up in dichloromethane, and insoluble constituents werefiltered off. After concentration of the filtrate, the residue waschromatographed on silica gel (CH₂Cl₂/methanol 95:5), resulting in 350mg of the desired morpholine derivative. After a further purification ona preparative HPLC it was possible to isolate 160 mg of thecorresponding trifluoroacetate in the form of a colorless solid.

Example 11[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-phenyl]-diethyl-amine,trifluoroacetate

The procedure was analogous to the method described in example 10starting from diethylamine and4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline(example 5, intermediate 3). Reaction time: 2 days at 100° C.; threetimes the amount of Pd catalyst and phosphine ligand. The desiredtrifluoroacetate can be isolated as a colorless solid after preparativeHPLC.

Example 126,8-Dichloro-2-methyl-4-(4-piperidin-1-yl-phenyl)-1,2,3,4-tetrahydro-isoquinoline,trifluoroacetate

The desired piperidine derivative can be obtained starting frompiperidine and4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline(example 5, intermediate 3) in analogy to the method described inexample 10.

Example 136,8-Dichloro-2-methyl-4-(4-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydroisoquinoline,hydrochloride

The reaction is carried out in analogy to the method described inexample 10, starting from pyrrolidine and4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline(example 5, intermediate 3). The product obtained after purification bychromatography is taken up in the DMSO/acetonitrile mixture, whereupon aprecipitate separates out. This is filtered off, dissolved in 2 N HCland freeze dried, resulting in the title compound of a colorless solid.

Example 146,8-Dichloro-2-methyl-4-[4-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-isoquinoline,trifluoroacetate

Reaction of N-methyl-piperazine and4-(4-bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline(example 5, intermediate 3) by the method described in example 10affords the title compound in the form of a colorless solid.

Example 156,8-Dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline,trifluoroacetate

Intermediate 1: Cyclopropyl-(2,4-dichloro-benzyl)-amine;

5.25 g (30 mmol) of 2,4-dichlorobenzaldehyde was introduced into 140 mlof methanol and, at room temperature, a solution of 1.71 g (30 mmol) ofcyclopropylamine was added. The mixture as stirred at room temperaturefor 40 min and then 1.42 g (37.5 mmol) of NaBH₄ was added in portions.After standing overnight, the solvent was removed and the residue wastaken up in 2 N HCl. Two extractions with ethyl acetate were carriedout. The aqueous phase was made alkaline with NaOH and again extractedtwice with ethyl acetate. The organic phases were dried with MgSO₄ andconcentrated. The crude product obtained in this way, in the form of aslightly yellowish oil, was reacted further without furtherpurification.

Intermediate 2:2-[Cyclopropyl-(2,4-dichloro-benzyl)-amino]-1-phenyl-ethanone;Intermediate 1 was reacted with alpha-bromoacetophenone in the presenceof triethylamine in dioxane by the method described in example 1,intermediate 3. For workup, the solvent was distilled off, and theresidue was taken up in ethyl acetate. It was washed twice with H₂O andtwice with 2 N HCl, dried with MgSO₄ and concentrated. The crude productobtained in this way was reacted further without further purification.

Intermediate 3:2-[Cyclopropyl-(2,4-dichloro-benzyl)-amino]-1-phenyl-ethanol;Intermediate 2 was reduced with NaBH₄ in analogy to the method describedin example 1, intermediate 4. For workup, the mixture was concentrated,and the residue was partitioned between 1 N HCl and ethyl acetate. Theaqueous phase was separated off and extracted once more with ethylacetate. The combined organic phases were dried with MgSO₄ and thesolvent was removed in vacuo.

6,8-Dichloro-2-cyclopropyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline,trifluoroacetate; Intermediate 3 (1.9 g) was dissolved without furtherpurification in 10 ml of dichloromethane and cyclized with conc. H₂SO₄by the method described in example 1. For workup, the reaction mixturewas poured onto ice. The organic phase was separated off, and theaqueous phase was extracted once more with dichloromethane. The combinedorganic phases were dried with MgSO₄ and freed of solvent.

Chromatography on silica gel (n-heptane/ethyl acetate 5:1→3:1) affords200 mg of a yellowish oil, which was subjected to further purificationon a preparative HPLC. This resulted in 184 mg of the title compound astrifluoroacetate.

Example 16 16a:(−)-N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide

16b:(+)-N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;

500 mg of the title compound from example 1 was separated on a chiralphase, resulting in about 250 mg of the two enantiomeric acetamides 16aand 16b.

-   -   chiral column: Chiralpak OD 250×4.6 mm;    -   solvent: acetonitrile;    -   flow rate: 1 ml/min;    -   R_(t)((−)-enantiomer/16a)=5.856 min;    -   R_(t)((+)-enantiomer/16b)=8.613 min.

Example 174-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine,hydrochloride

Intermediate 1:4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;3.0 g (8.6 mmol) ofN-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide(example 1) was dissolved in 100 ml of 20% strength sodium ethanolatesolution and heated under reflux for four hours. A further 2.0 g (29.4mmol) of solid sodium ethanolate was added, and the mixture was heatedunder reflux for three more hours. For workup, the solvent was removedin vacuo, and the residue was taken up in 200 ml of H₂O and extractedtwice with dichloromethane. The combined organic phases were dried withMgSO₄ and concentrated. Further purification by chromatography on silicagel (ethyl acetate/heptane 1:1) resulted in the aniline as a yellowishoil quantitative yield.

4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine,hydrochloride;

200 mg (0.65 mmol) of4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamineare dissolved in 30 ml of ethanolic HCl. The clear solution wasconcentrated in vacuo. The residue was triturated in ether, filtered offwith suction and dried, whereupon it was possible to isolate 208 mg ofthe desired hydrochloride.

Example 18N-Ethyl-N′-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonylurea,hydrochloride

1.0 mmol of4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzene-sulfonamide(example 4, intermediate 2) as mixed with 350 mg (2.5 eq) of K₂CO₃ in 15ml of dry acetone and stirred at room temperature for 1.5 hours. Asolution of 2.5 eq of ethyl isocyanate in acetone was added dropwise atroom temperature, and the solution was heated to reflux. For workup, themixture was concentrated in vacuo, and the residue was taken up in H₂Oand extracted twice with ethyl acetate. The aqueous phase was acidifiedwith 6 N HCl, and the resulting precipitate was filtered off withsuction. Washing with ethyl acetate and drying in vacuo afforded thetitle compound in good yield.

Example 191-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-propylurea

A solution of 0.17 g (2.0 mmol) of n-propyl isocyanate in toluene wasadded dropwise to a stirred solution of 500 mg (1.63 mmol) of4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine(see example 17) in 15 ml of toluene. After one hour at 40° C., afurther 0.17 g of n-propyl isocyanate was added, and the mixture wasstirred at 80° C. for one hour. For workup, the solvent was removed andthe residue was triturated with H₂O and ether. Drying affords 503 mg ofthe desired n-propylurea.

19a:1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-propyl-urea,hydrochloride;

450 mg of1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-propyl-ureawere dissolved in a mixture of 2 N HCl and THF. The clear solution wasconcentrated in vacuo, and the residue was triturated with ether andfiltered off with suction. Drying affords 473 mg of the desiredhydrochloride.

Example 201-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea

Proceeding in analogy to the method described in example 19 and startingfrom 500 mg (1.63 mmol) of4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine(see example 17) and 220 mg (3.0 mmol) of methyl isothiocyanate allowed245 mg of the desired thiourea to be isolated.

Example 211-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethylurea

Preparation takes place in analogy to a method described in example 19,starting from4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine(500 mg; 1.63 mmol) and ethyl isocyanate (284 mg/4 mmol).

21 a:1-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea,hydrochloride;

Conversion into the corresponding hydrochloride takes place in analogyto the method described in example 19a.

Example 22N-[4-(6-Methanesulfonyl-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide

Intermediate 1: (4-Methanesulfonyl-benzyl)-methyl-amine was synthesizedstarting from 1-bromomethyl-4-methanesulfonylbenzene and methylamine ina manner known to the skilled worker.

The title compound was prepared in analogy to the synthetic routeindicated in example 1, starting from(4-methanesulfonyl-benzyl)-methyl-amine (intermediate 1) andN-[4-(2-bromo-acetyl)-phenyl]-acetamide (example 1, intermediate 2).

Example 23N-[4-(2,6,8-Trimethyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide

The synthetic route detailed in example 1 was followed, starting from(2,4-dimethyl-benzyl)-methyl-amine, which can be prepared from1-bromomethyl-2,4-dimethyl-benzene and methylamine in a manner known tothe skilled worker, and N-[4-(2-bromo-acetyl)-phenyl]-acetamide (example1, intermediate 2).

Example 24N-[4-(6-Bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide

The synthetic route detailed in example 1 was followed, starting from(4-bromo-2-chloro-benzyl)-methyl-amine, which can be prepared from4-bromo-1-bromomethyl-2-chloro-benzene and methylamine in a manner knownto the skilled worker, and N-[4-(2-bromo-acetyl)-phenyl]-acetamide(example 1, intermediate 2).

Example 25N-[4-(8-Chloro-2-methyl-6-pyrrolidin-1-yl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide

1.02 g (3.12 mmol) of Cs₂CO₃, 8.8 mg (0.04 mmol) of palladium acetateand 36.1 mg (0.06 mmol) of 2,2-bis-diphenylphosphino-1,1-binaphthyl wasintroduced into 6.5 ml of abs. toluene under argon. At room temperature,a solution of 512 mg (1.3 mmol) ofN-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide(example 24) in 4 ml of abs. DMF, and a solution of 111 mg (1.56 mmol)of pyrrolidine in 4 ml of DMF were added, and the mixture was heated at100° C. for 7 hours. For workup, the solvent was removed in vacuo, andthe residue was taken up in dichloromethane. Insoluble constituents werefiltered off, and the filtrate was concentrated. The residue waschromatographed on silica gel with a dichloromethane/methanol mixture,and it is possible to isolate 360 mg of the compound of the example.

25a:N-[4-(8-Chloro-2-methyl-6-pyrrolidin-1-yl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide,hydrochloride;

320 mg ofN-[4-(8-chloro-2-methyl-6-pyrrolidin-1-yl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamidewas dissolved in 20 ml of ethanolic HCl, stirred at room temperature for30 min and concentrated. The residue was taken up in H₂O and freezedried.

Example 26N-[4-(8-Chloro-2-methyl-6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide,trifluoroacetate

Preparation takes place in analogy to the method described in example25, starting fromN-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide(example 24) and morpholine. The chromatography on silica gel wasfollowed by a further purification on a preparative HPLC.

Example 27N-{4-[8-Chloro-2-methyl-6-(4-methyl-piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinolin-4-yl]-phenyl}-acetamide

Preparation takes place in analogy to the method described in example25, starting fromN-[4-(6-Bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide(example 24) and N-methyl-piperazine.

27a:N-{4-[8-Chloro-2-methyl-6-(4-methyl-piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinolin-4yl]-phenyl}-acetamide,hydrochloride;

220 mg ofN-{4-[8-Chloro-2-methyl-6-(4-methyl-piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinolin-4-yl]-phenyl}-acetamidewas dissolved in a little methanol, diluted with 2 N HCl and freezedried, resulting in 226 mg of the desired hydrochloride.

Example 28N-{4-[8-Chloro-6-(cyclopropylmethyl-amino)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl]-phenyl}-acetamide,hydrochloride

Preparation takes place in analogy to the method described in example25, starting fromN-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide(example 24) and C-cyclopropyl-methylamine. The chromatography on silicagel was followed by a further purification on a preparative HPLC. Thepurified compound was dissolved in 1 N HCl, diluted with H₂O and freezedried.

Example 295-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoicacid

Intermediate 1: Ethyl 5-acetyl-2-hydroxy-benzoate was prepared from5-acetyl-2-hydroxy-benzoic acid by acid-catalyzed esterification in amanner known to the skilled worker.

Intermediate 2: Ethyl 5-(2-bromo-acetyl)-2-hydroxy-benzoate was preparedfrom ethyl 5-acetyl-2-hydroxy-benzoate by a known method in analogy tothe process described in example 1, intermediate 2.

Intermediate 3: Ethyl5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoate

The title compound was synthesized by the synthetic route described inexample 1, starting from ethyl 5-(2-bromo-acetyl)-2-hydroxy-benzoate and2,4-dichlorobenzyl-(methyl)-amine (see example 1, intermediate 1).

5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoicacid; 6.8 g (18 mmol) of ethyl5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoatewas hydrolyzed in an ethanol/2 N KOH mixture in a manner known to theskilled worker, resulting in 5.4 g of the free acid.

29a:5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoicacid, sodium salt;

352 mg (1 mmol) of the free acid5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoicacid was dissolved in 10 ml of 0.1 M NaOH, diluted with H₂O and freezedried, resulting in 375 mg of the title compound.

Example 305-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-N-methyl-benzamide,trifluoroacetate

The title compound was prepared starting from5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoicacid in a TOTU-mediated reaction with methylamine in analogy to themethod described in example 7.

Example 315-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-ethyl-2-hydroxy-benzamide,trifluoroacetate

The title compound was prepared starting from5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoicacid in a TOTU-mediated reaction with ethylamine in analogy to themethod described in example 7.

Example 325-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-N-(2-dimethylamino-ethyl)-2-hydroxy-benzamide,trifluoroacetate

The title compound was prepared starting from5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoicacid in a TOTU-mediated reaction with N1,N1-dimethyl-ethane-1,2-diaminein analogy to the method described in example 7.

Example 33N-[5-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoyl]-guanidine

2.52 g of potassium tert-butoxide was added to a solution of 2.39 g (25mmol) of guanidine hydrochloride in 15 ml of abs. DMF and stirred atroom temperature for 45 min. A solution of 950 mg (2.5 mmol) of ethyl5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-2-hydroxy-benzoate(example 29, intermediate 3) in 10 ml of abs. DMF was added, and themixture was stirred at room temperature for four hours. After no furtherincrease in conversion was detectable, the precipitate was removed byfiltration with suction and the solvent was removed in vacuo. Theresidue was taken up in 2 N HCl and extracted twice withdichloromethane. The aqueous phase was adjusted to a pH of about 10 withKOH, whereupon the desired acylguanidine separates out as a colorlessprecipitate. Filtration with suction and drying affords 793 mg of thetitle compound.

Example 34N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide

N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;The desired meta-substituted acetanilide was prepared in analogy to thesynthetic route indicated for example 1, starting fromN-(3-acetyl-phenyl)-acetamide and 2,4-dichlorobenzyl-(methyl)-amine(example 1, intermediate 1) in four analogous stages.

Example 353-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine

Acetyl was eliminated fromN-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide(example 34) by the method described in example 17, intermediate 1, inthe presence of sodium ethanolate.

Example 362-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine

Intermediate 1: N-[2-(2-Bromo-acetyl)-phenyl]-acetamide; 31 g (0.175mol) of N-(2-Acetylphenyl)-acetamide (prepared by acylation of2-aminoacetophenone with acetyl chloride as described by Fuerstner,Alois; Jumbam, Denis N.; Tetrahedron; 48; 29; 5991-6010, (1992)) wasdissolved in 200 ml of glacial acetic acid. 127 ml of 33% strength HBrin glacial acetic acid was added and then, at room temperature, 8.75 ml(0.175 mol) of bromine was slowly run in. The mixture was stirred atroom temperature overnight. The mixture was stirred into 1.5 l ofice-water, and the precipitated product was filtered off with suction,thoroughly washed with ice-water and dried in vacuo. The crude productcontained, according to HPLC and NMR, some precursor and dibrominatedproduct, but was pure enough (about 85% strength) for further reaction.

Yield: 43 g

Intermediate 2:N-(2-{2-[(2,4-Dichloro-benzyl)-methyl-amino]-acetyl}-phenyl)-acetamide;

12.4 g (65.24 mmol) of 2,4-dichloro-N-methylbenzylamine (example 1,intermediate 1) was dissolved in 200 ml of dioxane. To this was added19.96 g of the crude product from the preceding bromination, likewisedissolved in 200 ml of dioxane, and 45 ml of triethylamine. The mixturewas stirred at room temperature overnight and then filtered. Thefiltrate was evaporated, and the residue was taken up in ethyl acetateand washed with saturated sodium bicarbonate solution and brine, driedover sodium sulfate and concentrated in a rotary evaporator. The crudeproduct (20.4 g) was pure enough according to NMR for further reaction.

Intermediate 3:N-(2-{2-[(2,4-Dichloro-benzyl)-methyl-amino]-1-hydroxy-ethyl}-phenyl)-acetamide;

20 g of the crude product from the preceding stage (about 50 mmol) wasdissolved in 200 ml of methanol and cooled to <5° C. in an icebath. Tothis were added, while stirring vigorously, 4.3 g (109 mmol) of sodiumborohydride in portions so that the internal temperature does not exceed10° C. The mixture as then stirred in the icebath for 30 min and at RTfor 1 h. After standing overnight, the mixture was evaporated, and theresidue was taken up in ethyl acetate, washed 3× with water and 1× withbrine, dried over sodium sulfate and concentrated in a rotaryevaporator. The crude product (19.4 g) was reacted further withoutpurification.

Intermediate4:1-(2-Amino-phenyl)-2-[(2,4-dichloro-benzyl)-methyl-amino]-ethanol; 10g of the crude product from the preceding stage ere dissolved in 300 mlof methanol. 200 ml of conc. hydrochloric acid were added, and themixture was stirred at 50° C. for 10 h. The mixture was allowed to cooland was poured into water, and the pH was adjusted to 10-12 with 20%strength NaOH. The product was extracted with ethyl acetate, and thecombined extracts were washed with brine, dried over sodium sulfate andevaporated. The crude product (9.9 g) contained some sodium chloride,but this does not interfere with further reaction.

2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine;

9.9 g of the crude product from the preceding stage was dissolved in 350ml of chloroform. While cooling in an icebath, 123 ml of conc. sulfuricacid were added dropwise. The mixture was stirred in the icebath for 2 hand was then allowed slowly to reach RT and was finally heated at 50° C.overnight. The cooled mixture was poured onto ice and made alkaline(pH>10) with sodium hydroxide solution. The organic phase was separatedoff, the aqueous phase was back-extracted 2× with methylene chloride,and the combined organic phases were washed with water and NaCl, driedover sodium sulfate and evaporated.

General Method for Preparing the Compounds of Examples 37 to 77

154 mg (0.5 mmol) of the title compounds from example 35, example 36 orexample 17, intermediate 1, were introduced into 5 ml ofdichloromethane, and 0.076 ml (0.55 mmol) of triethylamine was added. At0° C., a solution of 1.1 equivalents (0.55 mmol,) of an acid chloride in5 ml of dichloromethane was added, and the mixture was stirred overnightwhile warming up. For workup, it was filtered and freed of solvent. Theresidue was dissolved in 20 ml of ethyl acetate and washed once eachwith 5% strength NaHCO₃ solution and 5% strength NaCl solution, anddried. Evaporation of the solvent was followed by final purification ona preparative HPLC. TABLE 1 Precursor 1/ Precursor 2/ Example anilineacid chloride Product 34

Ex. 17, Int. 1 38

Ex. 17, Int. 1 39

Ex. 17, Int. 1 40

Ex. 17, Int. 1 41

Ex. 17, Int. 1 42

Ex. 17, Int. 1 43

Ex. 17, Int. 1 44

Ex. 17, Int. 1 45

Ex. 17, Int. 1  46*

Ex. 17, Int. 1 47

Ex. 17, Int. 1 48

Ex. 17, Int. 1 49

Ex. 17, Int. 1 50

Ex. 17, Int. 1 51

Ex. 35 52

Ex. 35 53

Ex. 35 54

Ex. 35 55

Ex. 35 56

Ex. 35 57

Ex. 35 58

Ex. 35 59

Ex. 35 60

Ex. 35 61

Ex. 35 62

Ex. 35 63

Ex. 35 64

Ex. 35 65

Ex. 36 66

Ex. 36 67

Ex. 36 68

Ex. 36 69

Ex. 36 70

Ex. 36 71

Ex. 36 72

Ex. 36 73

Ex. 36 74

Ex. 36 75

Ex. 36 76

Ex. 36 77

Ex. 36*Product precipitates from the reaction solution and requires no furtherpurification

Example 781-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea,trifluoroacetate

0.355 mmol of the compound of example 35 was dissolved in 5 ml of dryacetonitrile, and 0.39 mmol of ethyl isocyanate was added. Afterstanding overnight with exclusion of moisture, the solvent was removedand the crude product was purified on a preparative HPLC, resulting inthe title compound as a colorless solid.

Example 791-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea,trifluoroacetate

The title compound was synthesized starting from the compound of example35 and methyl isothiocyanate by the method described in example 78.

Example 801-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea

The process is analogous to example 78, starting from the compound ofexample 36 and ethyl isocyanate. For workup, the resulting precipitatewas filtered off with suction and washed with acetonitrile, resulting inthe desired ethylurea as a colorless solid.

Example 811-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-methyl-thiourea,trifluoroacetate

The compound of example 36 and methyl isothiocyanate are reacted inanalogy to the method described in example 78.

Example 82N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-ethanesulfonamide,hydrochloride

307.1 mg (1 mmol) of the compound of example 35 was dissolved in 10 mlof pyridine and at 0° C., 0.19 g (1.5 mmol) of ethanesulfonyl chloride,and a catalytic amount of DMAP are added. The mixture was stirred atroom temperature.

For workup, the solvent was removed in vacuo, the residue was taken upin ethyl acetate and washed with H₂O. The organic phase was dried withMgSO₄ and concentrated. The crude product was chromatographed on silicagel. The sulfonamide obtained in this way was dissolved in a THF/2 N HClmixture and again concentrated in vacuo, resulting in 208 mg of thedesired hydrochloride.

Example 83N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide,hydrochloride

The process is analogous to the method described in example 82, startingfrom the compound of example 35 and methanesulfonyl chloride.

Example 84N-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-ethanesulfonamide,hydrochloride

The process is analogous to the method described in example 82, startingfrom the compound of example 17, intermediate 1, and ethanesulfonylchloride.

Example 85N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide,hydrochloride

The process is analogous to the method described in example 82, startingfrom the compound of example 17, intermediate 1, and methanesulfonylchloride.

Example 86 86a:(−)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide

86b:(+)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide;

2.0 g of the title compound from example 34 were separated on a chiralphase, resulting in about 1.0 g of the two enantiomeric acetamides 86aand 86b.

-   -   chiral column: Chiralpak ADH/31 250×4.6 mm;    -   solvent: acetonitrile;    -   flow rate: 1 ml/min;    -   R_(t)((−)-enantiomer/86a)=5.541 min;    -   R_(t)((+)-enantiomer/86b)=7.033 min.

General Method for Preparing the Compound of Examples 87 to 98

1.0 mmol of4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine(example 17, intermediate 1) or3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine(example 35) was introduced into 10 ml of pyridine and, at 0° C., asolution of 1.2 equivalents of the appropriate sulfonyl chloride (seetable 2) in 5 ml of dichloromethane was added dropwise. The mixture asstirred at room temperature. A catalytic amount of DMAP was addeddepending on the progress of the reaction and, where appropriate, thereaction temperature was increased to 50° C. until no further increasein conversion can be detected. For workup, the mixture was concentratedand the residue was partitioned between ethyl acetate and saturatedNaHCO₃ solution. The organic phase was separated off and washed oncemore with saturated NaHCO₃ solution and H₂O, dried with Na₂SO₄ andconcentrated. For further purification, the crude product obtained inthis way was chromatographed on silica gel. The products obtained inthis way were converted into the corresponding hydrochlorides bydissolving the substances in 2 N HCl or ethanolic HCl and freeing offsolvent, resulting in the desired HCl salts.

Purification in a preparative HPLC system results in the correspondingproducts as trifluoroacetates. TABLE 2 Precursor 1/ Precursor 2/ Exampleaniline acid chloride Product 87

Ex. 17, Int. 1 88

Ex. 17, Int. 1  88a

Ex. 17, Int. 1 89

Ex. 17, Int. 1  89a

Ex. 17, Int. 1 90

Ex. 17, Int. 1  90a

Ex. 17, Int. 1 91

Ex. 17, Int. 1  91a

Ex. 17, Int. 1 92

Ex. 17, Int. 1  92a

Ex. 17, Int. 1 93

Ex. 35 94

Ex. 35  94a

Ex. 35 95

Ex. 35 96

Ex. 35  96a

Ex. 35 97

Ex. 35  97a

Ex. 35 98

Ex. 35

General Method for Synthesizing the Compounds of Examples 99 to 110

Preparation of the Amine Component

4.0 mmol of the aromatic amine (see table 3) was stirred with 8.0 mmolof the aliphatic aldehyde (see table 3) in methanol at room temperaturefor 2 hours and then, depending on the progress of the reaction, 0.67 to2.0 eq of NaBH₄ was added in portions. After standing at roomtemperature overnight, the solvent was removed and the residue was takenup in 1 N HCl. It was extracted with dichloromethane. The aqueous phasewas adjusted to a pH of 11 to 12 with NaOH and again extracted withdichloromethane. The organic phases were dried with MgSO₄ andconcentrated in a rotary evaporator. Further purification takes place bychromatography on silica gel or on a preparative HPLC.

Preparation of the Bromo Ketone Component

The bromo ketone building blocks was synthesized by methods known fromthe literature, starting from commercial acetophenones by treatment withbromine in glacial acetic acid in analogy to example 1, intermediate 2.

The compounds of examples 100 to 111 were prepared starting from theamine and bromo ketone components shown in table 3 in analogy to thesynthetic route shown in example 1 (alkylation of the amine component bythe bromo ketone component, subsequent reduction with NaBH₄ and finalH₂SO₄-mediated cyclization).

The resulting tetrahydroisoquinolines was converted into thecorresponding salts in a manner known to the skilled worker. TABLE 3Example Aromatic Aliphatic Bromo ketone No. aldehyde amine Aminecomponent component Compound of example 99

—NH₂

*)

100

—NH₂

101

—NH₂

102

103

—NH₂

104

105

—NH₂

106

—NH₂

107

—NH₂

108

—NH₂

109

—NH₂

110

—NH₂

*)Synthesis described in: Lang et al., DE-A 24 36 263

Standard Procedure for the Preparation of the Example Compounds 111 to124

0.358 mmol of the acid component, which are listed in table 4, weredissolved in 1 ml DMF and 0.221 ml (1.30 mmol) of Diisopropylethylaminewere added. At 0° C. a solution of 128 mg (0.390 mmol) TOTU was addedfollowed by a solution of the amine component, listed in table 4. Afterthe resulting solution was kept at room temperature overnight, thereaction mixture was filtered and the filter was washed with 20 ml ofethyl acetate. The filtrate was washed twice with sat. NaHCO₃-sol.,followed by 5% NaCl-sol. The organic layers were dried using MgSO₄ andthe solvent evaporated i. vac. The obtained crude products, which stillcontained Boc-protecting groups, were deprotected following theprocedure given below, without further purification. The above obtainedcrude products, which were not Boc-protected were purified on a HPLC, bywhich the example compounds were obtained as the correspondingTrifluoroacetates.

Standard Procedure for the Preparation of the Example Compounds 125 to147

0.358 mmol of the acid component, which were listed in table 4, weredissolved in 1 ml DMF and 0.221 ml (1.30 mmol) of Diisopropylethylaminewere added. At 0° C., 151 mg (0.975 mmol) Diethylcarbodiimide, asolution of 132 mg (0.975 mmol) HOBt in 1 ml DMF and 20 mg (0.162 mmol)DMAP were added, followed by a solution of the amine component, listedin table 4, in 2 ml DMF. The solution was kept at room temperatureovernight. For the working up, the reaction mixture was filtered and thefilter was washed with 20 ml of ethyl acetate. The filtrate was washedtwice with sat. NaHCO₃-sol., followed by 5% NaCl-sol. The organic layerswere dried using MgSO₄ and the solvent evaporated i. vac. The obtainedcrude products, which still contained Boc-protecting groups, weredeprotected following the procedure given below, without furtherpurification. The above obtained crude products, which were notBoc-protected were purified on a HPLC, by which the example compoundswere obtained as the corresponding Trifluoroacetates.

Standard Procedure for the Deprotection of the Boc-Groups:

The obtained crude products were dissolved in 5 ml of a 10% solution ofTrifluoro-acetic acid in Dichloromethane for 1 h at room temperature.The reaction mixture was evaporated i. vac. and the resulting residueswere purified by HPLC. The example compounds were obtained as Trifluoroacetates. TABLE 4 Example-No. Acid component Amine component Examplecompound 111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

Example 1481-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-thiourea-HydrochlorideSalt

2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine(95 mg, example 36) was dissolved in acetonitrile (4 ml) andisothiocyanato-ethane (27 mg) was added to the stirred solution. Afterstanding for 15 h at room temperature the solvent was removed and theresidue purified by preparative HPLC. The product containing fractionswere combined and the acetonitrile was removed in vaccuo. After additionof potassium carbonate the aqueous phase was extracted with ethylacetate. The organic layer was separated, dried (magnesium sulphate),filtered and concentrated in vaccuo. The residue was dissolved inwater/2N hydrochloric acid and freeze dried to give 36 mg of the titlecompound.

Example 1491-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-thiourea—Hydrochloridesalt

4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine(50 mg, example 17, intermediate 1) was dissolved in tetrahydrofurane (4ml) and isothiocyanato-ethane (14 mg) was added to the stirred solution.After 2 h at reflux temperature the solution was concentrated and theresidue kept for 2 h at 85° C. The crude product was purified bypreparative HPLC. The product containing fractions were combined and theacetonitrile was removed in vaccuo. After addition of potassiumcarbonate the aqueous phase was extracted with ethyl acetate. Theorganic layer was separated, dried (magnesium sulphate), filtered andconcentrated in vaccuo. The residue was dissolved in water/2Nhydrochloric acid and freeze dried to give 33 mg of the title compound.

Example 1501-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-thiourea—Trifluoroaceticacid salt

3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine(50 mg, example 35) was dissolved in tetrahydrofurane (3 ml) andisothiocyanato-ethane (14 mg) was added to the stirred solution. After 2h at reflux temperature the solution was concentrated and the residuekept for 2 h at 85° C. The crude product was purified by preparativeHPLC. The product containing fractions were combined and the solvent wasremoved in vaccuo to give 66 mg of the title compound.

Example 1513-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-dimethyl-urea—Hydrochloridesalt

Intermediate 1:[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 4-nitro-phenyl ester—Hydrochloride salt

3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine(350 mg, example 35) was dissolved in dichloromethane (17.5 ml) and4-nitrophenyl-chloroformate (230 mg) was added to the stirred solution.After 4.5 h an additional 0.1 equivalents of 4-nitrophenyl-chloroformate(23 mg) was added and the mixture stirred over night. The precipitatewas removed by suction, washed with dichloromethane and dried undervacuum. The product (545 mg) was used in the next step without furtherpurification.

3-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,1-dimethyl-urea—Hydrochloride salt

[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 4-nitro-phenyl ester—Hydrochloride salt (35 mg) was suspended indichloromethane (3.5 ml). Under stirring dimethylamine (3.7 mg)dissolved in dichloromethane (1 ml) was added. After 1 hdichloromethane, water and saturated potassium carbonate solution wereadded. The organic layer was separated, washed two times with saturatedpotassium carbonate solution, dried over magnesium sulphate, filteredand concentrated in vacuo. The residue was dissolved in water/2Nhydrochloric acid and freeze dried to give 29 mg of the title compound.

The following examples were synthesised analogously to example 4 usingthe respective amine. Sometimes preparative HPLC purification wasrequired. TABLE 5 Example Structure 152

153

154

155

156

157

158

The following examples were prepared analogously to example 151. But THFwas used as solvent in a closed vial. For examples 159 and 166 areaction temperature of 85° C. was required. Example 20 requiredpreparative HPLC purification. TABLE 6 Example Structure 159

160

161

162

163

164

165

166

167

Example 168 4-Methyl-piperazine-1-carboxylic acid[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide—Hydrochloridesalt

Intermediate1:[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 4-nitro-phenyl ester—Hydrochloride salt

2(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine(200 mg, example 36) was dissolved in dichloromethane (10 ml) and4-nitrophenyl-chloroformate (131 mg) was added to the stirred solution.After 3.5 h the precipitate was removed by suction, washed withdichloromethane and dried. The crude material was re-crystalized fromdichloromethane to give 159 mg of the title compound.

4-Methyl-piperazine-1-carboxylic acid[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide—Hydrochloridesalt

[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 4-nitro-phenyl ester—Hydrochloride salt (15 mg) was suspended indichloromethane (2 ml). Under stirring 1-methyl-piperazine (3.2 mg)dissolved in dichloromethane (1 ml) was added. After 1 hdichloromethane, water and saturated potassium carbonate solution wereadded. The organic layer was separated, washed two times with saturatedpotassium carbonate solution, dried over magnesium sulphate, filteredand concentrated in vacuo. The residue was dissolved in water/2Nhydrochloric acid and freeze dried to give 13 mg of the title compound.

The following examples were synthesised analogously to example 168:TABLE 7 Example Structure 169

170

171

172

173

174

175

Example 176 4-Methyl-piperazine-1-carboxylic acid[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide—Hydrochloridesalt

Intermediate 1:[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 4-nitro-phenyl ester—Hydrochloride salt

4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine(200 mg, example 17, intermediate 1) was dissolved in dichloromethane(10 ml) and 4-nitrophenyl-chloroformate (131 mg) was added to thestirred solution. After 4.5 h the precipitate was removed by suction,washed with dichloromethane and dried. The crude material wasre-crystalized twice from dichloromethane to give 254 mg of the titlecompound.

4-Methyl-piperazine-1-carboxylic acid[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-amide—Hydrochloridesalt

[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 4-nitro-phenyl ester—Hydrochloride salt (15 mg) was suspended indichloromethane (2 ml). Under stirring 1-methyl-piperazine (3.2 mg)dissolved in dichloromethane (1 ml) was added. After 5 h of stirring andstanding over night dichloromethane, water and saturated potassiumcarbonate solution were added. The organic layer was separated, washedtwo times with saturated potassium carbonate solution, dried overmagnesium sulphate, filtered and concentrated in vacuo. The residue wasdissolved in water/2N hydrochloric acid and freeze dried to give 13 mgof the title compound.

The following examples were synthesised analogously to example 176:TABLE 8 Example Structure 177

178

179

180

181

182

183

Example 184N-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phen{circumflexover ( )}-yl]-formamide—Hydrochloride salt

4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine(200 mg, example 17, intermediate 1) was dissolved in formic acid (1 ml)and kept for 15 min at reflux temperature. After standing over night anice/water mixture was added followed by ethyl acetate. After separatingthe organic layer the aqueous phase was again extracted with ethylacetate. The combined organic layers were dried (magnesium sulphate),filtered and concentrated in vacuo. The residue was dissolved in amixture of dichloromethane and saturated sodium bicarbonate solution.The organic layer was separated and the aqueous phase was extracted 3times with dichloromethane. The organic layers were combined, dried(magnesium sulphate), filtered and concentrated in vacuo to yield 167 mgcrude material. 10 mg of this material was dissolved in water/2Nhydrochloric acid and freeze dried to give 11 mg of the title compound.

Example 185[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine—Hydrochloridesalt

At 50° C. under stirring and argon atmosphereN-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-formamide(150 mg, example 27) dissolved in tetrahydrofurane (2.5 ml) was added toa 1 M solution of lithium aluminiumhydride in tetrahydrofurane (0.45 ml)diluted with tetrahydrofurane (2.5 ml). After the addition the mixturewas heated to reflux temperature for 1 h. After standing over night atroom temperature the mixture was heated to 50° C. and further lithiumaluminiumhydride solution (0.22 ml) was added. The mixture was heated toreflux temperature and after 1 h the mixture was cooled, ice added andthe tetrahydrofurane removed in vaccuo. The residue was dissolved indichloromethane and hydrochloric acid. The aqueous layer was extractedthree times with dichloromethane, the organic layers were combined,dried (magnesium sulphate) and concentrated. The crude material waspurified by preparative HPLC. The product containing fractions werecombined and the acetonitrile was removed in vaccuo. After addition ofsodium bicarbonate the aqueous phase was extracted with dichloromethane.The organic layer was separated, dried (magnesium sulphate), filteredand concentrated in vaccuo to yield 80 mg of the salt free base. 10 mgof the base was dissolved in water/2N hydrochloric acid and freeze driedto give 10 mg of the title compound.

Example 1861-[4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-1,3-dimethyl-urea—Hydrochloridesalt

A002955438A

Following the procedure described in example 151 using[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine,4-nitrophenyl-chloroformate and methylamine (20 μl, 2 molar in THF) 9 mgof the title compound was obtained.

The following examples were synthesised analogously to example 186:TABLE 9 Example Structure 187

188

189

190

191

192

193

Example 194N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl)-formamide

3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine(600 mg, example 35) was dissolved in formic acid (2.4 ml) and kept for15 min at reflux temperature. After standing over night an ice/watermixture was added followed by ethyl acetate and saturated sodiumbicarbonate solution. The organic layer was separated and the aqueousphase was extracted 3 times with dichloromethane. The organic layerswere combined, dried (magnesium sulphate), filtered and concentrated invacuo to yield 588 mg of the title compound.

Example 195[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine—Hydrochloridesalt

At 50° C. under stirring and argon atmosphereN-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-formamide(588 mg, example 194) dissolved in tetrahydrofurane (10 ml) was added toa 1 M solution of lithium aluminiumhydride in tetrahydrofurane (1.8 ml).After the addition the mixture was heated to reflux temperature for 1 h.After standing over night at room temperature the mixture was heated to50° C. and further lithium aluminiumhydride solution (2 ml) added. Themixture was heated to reflux temperature and after 0.5 h the mixture wascooled and ice added. The aqueous phase was 4 times extracted with ethylacetate. The organic layers were combined, dried (magnesium sulphate)and concentrated. The crude material was purified by preparative HPLC.The product containing fractions were combined and the acetonitrile wasremoved in vaccuo. After addition of sodium bicarbonate the aqueousphase was extracted with ethyl acetate. The organic layer was separated,dried (magnesium sulphate), filtered and concentrated in vaccuo to yield270 mg of the salt free base. 45 mg of the base was dissolved inwater/2N hydrochloric acid and freeze dried to give 45 mg of the titlecompound.

Following the procedure described in example 151 using[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methyl-amine,4-nitrophenyl-chloroformate and the respective amine the following ureaderivatives were prepared: TABLE 10 Example Structure 196

197

198

199

200

201

202

203

Example 204[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 2-dimethylamino-ethyl ester—Hydrochloride salt

Under stirring and argon atmosphere[3-(6,8-dichloro-2-methyl--1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid 4-nitro-phenyl ester—hydrochloride salt (15 mg, example 151,intermediate 1) was suspended in dichloromethane (1.5 ml) and2-dimethylamino-ethanol (3 mg) dissolved in dichloromethane (0.5 ml) wasadded. After stirring for 6 h and standing over night dichloromethane,water and saturated potassium carbonate solution were added. The organiclayer was separated, washed three times with saturated potassiumcarbonate solution, dried over magnesium sulphate, filtered andconcentrated in vacuo. The crude material was purified by preparativeHPLC. The product containing fractions were combined and theacetonitrile was removed in vaccuo. After addition of sodium bicarbonatethe aqueous phase was extracted with ethyl acetate. The organic layerwas separated, dried (magnesium sulphate), filtered and concentrated invaccuo. The residue was dissolved in water/2N hydrochloric acid andfreeze dried to give 5 mg of the title compound.

Following the procedure described in the example above the followingcarbamates were prepared starting from2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamineand4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine,respectively. TABLE 11 Example Structure 205

206

Example 207[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamicacid methyl ester—Hydrochloride salt

Under stirring and argon3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine(15 mg, example 35) was dissolved in dichloromethane (1.5 ml) and methylchloroformate (4.6 mg) dissolved in dichloromethane (0.5 ml) was added.After stirring for 6 h and standing over night additional chloro formate(2.3 mg) was added. Stirring was continued for 5 h, then the solvent wasremoved and the residue was dissolved in water/2N hydrochloric acid andfreeze dried to give 20 mg of the title compound.

Following the procedure described in the example above the followingcarbamates were prepared starting from3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamineand4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine,respectively. TABLE 12 Example Structure 208

209

210

211

212

213

214

Example

215a:(+)-N-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide—Hydrochloridesalt

215b:(−)-N-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide—Hydrochloridesalt

RacemicN-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-methanesulfonamide(96 mg, example 83) was resolved by chiral preparative HPLC.

-   -   Chiral phase: Chiralpak AD 250×50 mm; 20μ;    -   Solvent: Heptane:Ethanol:Methanol: 10:1:1;    -   Flow rate: 50 ml/min

The residue was dissolved in water/2N hydrochloric acid and freeze driedto give 37 mg of the first eluting and 37 mg of the second elutingenantiomer.

The enantiomeric purity was determined by analytical HPLC.

-   -   column: Chiralpak AD-H/31 250×4.6 mm    -   mobile Phase: heptane:ethanol:methanol 10:1:1, flow: 1 m/min.    -   First eluting enantiomer: 6.84 min, 100% ee, MS (ES⁺, M+H⁺):        385.2    -   Second eluting enantiomer: 8.02 min, 100% ee, MS (ES⁺, M+H⁺):        385.2

Example

216a:(+)-1-[2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea—Hydrochloridesalt

216b:(−)-1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea—Hydrochloridesalt

Racemic1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-3-ethyl-urea(316 mg, example 80) were resolved by chiral preparative HPLC.

-   -   Chiral phase: Chiralpak OD 250×50 mm; 20μ;    -   Solvent: Heptane:Ethanol:iso-Propanol: 10:1:1; 0.3%        Diethylamine;    -   Flow rate: 50 m/min

The enantiomers were separately further purified using preparative HPLC.The product containing fractions were combined and the acetonitrile wasremoved in vaccuo. After addition of sodium bicarbonate the aqueousphase was extracted with ethyl acetate.

The organic layer was separated, dried (magnesium sulphate), filteredand concentrated in vaccuo. The residue was dissolved in water/2Nhydrochloric acid and freeze dried to give 37 mg of the first elutingand 58 mg of the second eluting enantiomer.

The enantiomeric purity was determined by analytical HPLC.

-   -   column: Chiralpak OD-20 250×4.6 mm    -   mobile Phase: heptane:ethanol:iso-propanol 50:2:1 (+0.3%        diethylamine), flow: 1 ml/min.    -   First eluting enantiomer: 9.22 min, 100% ee, MS (ES⁺, M+H⁺):        378.1    -   Second eluting enantiomer: 9.96 min, 98% ee, MS (ES⁺, M+H⁺):        378.1

Example 217N-[3-(6,8-Difluoro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide—Hydrochloridesalt

Intermediate 1: 2,4-Difluorobenzyl-methyl-amine was prepared startingfrom 2,4-Difluoro-benzaldehyd by standart procedures.

N-[3-(6,8-Difluoro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide—Hydrochloridesalt

Starting from N-(3-Acetyl-phenyl)-acetamide and2,4-Difluorobenzyl-methyl-amine (intermediate 1) the title compound wasprepared following the procedure described in example 1.

Example 2184-(3-Bromo-phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline—Hydrochloridesalt

Following the procedure described in example 1 starting from2,4-dichloro-benzaldehyde and using 2-bromo-1-(3-bromo-phenyl)-ethanoneas alkylating reagent 780 mg of the title compound was obtained.

Example 2191-[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline-4-yl)-phen-yl]-3-(2-hydroxy-ethyl)-urea

509 mg (1,0 mmol)[3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic-acid4-nitro-phenyl-ester-Hydrochloride (example 151, intermediate 1) weredissolved in 15 ml DMF and at 0° C. a solution of 67,2 mg (1,1 mmol) of2-Aminoethanol in 10 ml DMF was added. After stirring for 3 h at roomtemperature the solvent was removed i. vac. The residue was dissolved inethylacetate and washed with sat. NaHCO₃-solution. The organic layer wasseparated and the aqueous layer was extracted twice with ethylacetate.The combined organic layers were washed with sat. NaCl-solution, dried(MgSO4) and concentrated. Purification by silica gel chromatography(dichloromethane/methanol) yielded 265 mg of the title compound.

Example 2203-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline-4-yl)-benzoic-acid-ethyl-ester

Intermediate 1: 3-Acetyl-benzoic-acid can be prepared by literatureprocedures.

Intermediate 2: 3-Acetyl-benzoic-acid-ethyl-ester can be synthesizedstarting from Intermediate 1 by standart procedures.

Intermediate 3: 3-(2-Bromo-acetyl)-benzoic-acid-ethyl-ester was preparedanaloguosly to Example 1, Intermediate 2, starting from3-Acetyl-benzoic-acid-ethyl-ester (Intermediate 2).

3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline-4-yl)-benzoic-acid-ethyl-esterStarting from 3-(2-Bromo-acetyl)-benzoic-acid-ethyl-ester (Intermediate3) and Dichloro-benzyl-methyl-amine (Example 1, Intermediate 1), thetitle compound can be prepared by the methode described in example 1.

Example 2213-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline-4-yl)-benzoic-acid

500 mg3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinoline-4-yl)-benzoic-acid-ethyl-ester(Example 220) were dissolved in 15 ml methanol and treated with 10 ml ofa 2 N KOH-solution. After 1 h at 50° C. the solvent was removed i. vac.The residue was taken up in water and was washed with ether. The aqueousphase was seperated and 2 N HCl was added until a pH-value of about 6was reached. The precipitate was filtered off by suction and dried togive 304 mg of the title compound.

Analytical data for the compounds of examples 1 to 221: TABLE 13 R_(t)MS Ex. Structure [min] Method MS [M + H⁺] Method  1

1,60 B 349,1/350,1/ 351,0 ESI m.p.: 205-206° C.   1a

1,60 B 349,2/351,2 ESI m.p.: 125° C. (decomp.)   2a

3,63 A 371,3/373,3 412,3/414,3 ESI (+)-enantiomer   2b

3,67 A 371,3/373,3 412,3/414,3 ESI (+)-enantiomer   2c

3,66 A 371,1/373,1 412,1/414,1 ESI (−)-enantiomer   2d

1,56 B 371,1/373,1 412,1/414,1 ESI (−)-enantiomer  3

4,00 A 399,1/401,1 CI   4a

3,59 A 371,2/373,2 412,2/414,2 ESI   4b

1,58 B 371,0/372,0/ 373,0/373,9 ESI  5

4,57 A 369,9/371,9/ 373,9 CI  6

4,03 A 336,1/338,1 CI  7

4,17 A 363,3/365,3 CI  8

1,88 B 377,3/379,3 CI  9

1,45 B 406,3/408,3 CI  10

4,37 A 377.1/379,1 CI  11

4,05 A 363,2/365,2 ESI  12

3,79 A 375,2/377,2 ESI  13

4,92 A 361,2/363,2 ESI  14

4,08 A 390,2/392,2 ESI  15

4,80 A 318,2/320,2 CI  16a

1,61 B 349,1/350,1/ 351,1 ESI (−)-enantiomer  16b

1,61 B 349,1/350,1/ 351,1 ESI (+)-enantiomer  17

0,91 B 307,1/309,0 ESI  18

1,63 B 442,0/444,0 ESI  19

4,00 A 392,2/394,2 ESI  19a

1,80 B 392,1/394,1 ESI  20

1,67 B 380,1/382,2 ESI  21

1,68 B 378,3/380,2 ESI m.p.: 218-220°°C.  21a

1,68 B 378,1/379,1/ 380,1 ESI  22

0,32 B 359,1 717,3/718,3/ 719,3 ESI  23

1,60 B 309,2/310,1 ESI  24

1,67 B 393,0/394,0/ 396,0/397,0 ESI  25

1,85 B 384,1/386,1 ESI  25a

1,78 B 384,1/385,1/ 386,2 ESI  26

1,46 B 400,1/401,2/ 401,2 ESI  27

0.27 B 413,2/414,2/ 415,2 ESI  27a

0,25 B 413,2/414,2/ 415,2 ESI  28

1,65 B 384,2/385,2 386,2 ESI  29

1,67 B 352,0/353,0/ 354,0 ESI  29a

1,68 B 352,0/353,0/ 354,0 ESI  30

1,68 B 365,1/366,1/ 367,0/368,0 ESI  31

1,79 B 379,1/380,1/ 381,1 ESI  32

1,47 B 422,1/423,1/ 424,1/425,1 ESI  33

1,46 B 393,1/394,1/ 395,1 ESI  34

1,63 B 349,0/350,1/ 351,0 ESI  35

1,17 B 307,0/308,1/ 309,1 ESI  36

1,66 B 307,0/308,0/ 309,1 ESI  37

2,35 C 363,3/365,3 ESI  38

2,43 C 377,3/379,3 ESI  39

2,49 C 391,3/393,3 ESI  40

2,43 C 377,3/379,3 ESI  41

2,48 C 391,3/393,3 ESI  42

2,40 C 375,3/377,3 ESI  43

2,45 C 389,3/391,3 ESI  44

2,52 C 403,4/405,4 ESI  45

2,49 C 403,2/404,2 ESI  46

2,36 C 460,4/462,4 ESI  47

2,35 C 412,2/414,3 ESI  48

2,29 C 385,3/387,3 ESI  49

2,37 C 399,3/401,3 ESI  50

2,42 C 414,4/416,4 ESI  51

2,37 C 363,3/365,3 ESI  52

2,44 C 377,3/379,3 ESI  53

2,51 C 391,3/393,3 ESI  54

2,44 C 377,3/379,3 ESI  55

2,49 C 391,3/393,3 ESI  56

2,41 C 375,3/377,3 ESI  57

2,47 C 389,3/391,3 ESI  58

2,52 C 403,4/405,4 ESI  59

2,48 C 403,2/404,2 ESI  60

2,34 C 460,4/462,4 ESI  61

2,36 C 412,2/414,3 ESI  62

2,32 C 385,3/387,3 ESI  63

2,38 C 399,3/401,3 ESI  64

2,41 C 414,4/416,4 ESI  65

2,30 C 363,3/365,3 ESI  66

2,41 C 377,3/379,3 ESI  67

2,52 C 391,3/393,3 ESI  68

2,41 C 377,3/379,3 ESI  69

2,45 C 391,3/393,3 ESI  70

2,36 C 375,3/377,3 ESI  71

2,44 C 389,3/391,3 ESI  72

2,51 C 403,4/405,4 ESI  73

2,70 C 403,2/404,2 ESI  74

2,30 C 460,4/462,4 ESI  75

2,41 C 385,3/387,3 ESI  76

2,49 C 399,3/401,3 ESI  77

2,55 C 414,4/416,4 ESI  78

1,72 B 378,3/380,3 ESI  79

1,74 B 380,3/382,3 ESI  80

1,75 B 378,3/380,3 ESI  81

1,68 B 380,3/382,3 ESI  82

1,71 B 399,0/400,0/ 401,0/402,0/ 403,0 ESI  83

1,66 B 385,0/386,0/ 387,0 ESI  84

1,69 B 399,0/400,0/ 401,0/402,0 ESI  85

1,64 B 385,0/386,0/ 387,0/388,0 ESI  86a

1,64 B 349,3/351,3 ESI (−)-enantiomer  86b

1,63 B 349,3/351,3 ESI (+)-enantiomer  87

1,97 B 439,0/441,1 ESI  88

1,83 B 453,0/455,0 ESI  88a

1,83 B 453,0/455,0 ESI  89

2,01 B 531,0/533,0/ 534,9 ESI  89a

2,02 B 531,0/533,0/ 534,9 ESI  90

1,78 B 525,1/527,1 ESI  90a

1,79 B 525,1/527,1 ESI  91

1,63 B 465,1/467,1 ESI  91a

1,64 B 465,1/467,1 ESI  92

1,81 B 499,1/501,1/ 503,1 ESI  92a

1,82 B 499,1/501,1/ 503,1 ESI  93

1,99 B 439,0/441,1 ESI  94

1,87 B 453,0/455,0 ESI  94a

1,87 B 453,0/455,0 ESI  95

2,01 B 531,0/533,0/ 535,0 ESI  96

1,75 B 525,0/527,0 ESI  96a

1,75 B 525,0/527,0 ESI  97

1,66 B 465,0/467,0 ESI  97a

1,66 B 465,0/467,0 ESI  98

1,81 B 499,1/501,1/ 503,1 ESI  99

405,1/407,1 ESI m.p.: 122° C. 100

4,44 A 292,2/294,2 CI s. Ex. 2; Intermediate 4  100a

s. Ex. 2; Intermediate 4a  100b

s. Ex. 2; Intermediate 4b 101

4,43 A 326,0/328,0 ESI 102

4,23 A 306,1/308,0 ESI 103

2,84 C 360,0 ESI 104

2,79 C 320,0/322,0 ESI 105

2,64 C 291,9/293,9 ESI 106

4,26 A 310,0/312,0 ESI 107

4,43 A 306,1/308,1 ESI 108

4,11 A 292,0/294,0 ESI 109

4,28 A 292,0/294,0 ESI 110

4,05 A 302,0/304 ESI 111

1,37 D 364,4/366,4 ESI 112

1,44 D 378,4/380,4 ESI 113

1,51 D 392,4/394,4 ESI 114

1,51 D 378,3/380,3 ESI 115

1,58 D 392,4/394,4 ESI 116

1,04 D 435,5/437,5 ESI 117

1,67 D 404,4/406,4 ESI 118

2,08 D 412,3/414,3 ESI 119

2,27 D 400,4/402,4 ESI 120

2,37 D 400,4/402,4 ESI 121

1,54 D 432,5/434,5 ESI 122

1,70 D 428,5/430,5 ESI 123

2,55 D 445,4/447,4 ESI 124

2,43 D 428,5/430,5 ESI 125

1,88 D 401,4/403,4 ESI 126

2,31 D 496,5/498,5 ESI 127

2,14 D 429,4/431,4 ESI 128

2,07 D 401,4/403,4 ESI 129

2,44 D 469,4/471,4 ESI 130

1,55 D 378,4/380,4 ESI 131

1.52 D 392,4/394,4 ESI 132

1,63 D 378,3/380,3 ESI 133

1,64 D 392,4/394,4 ESI 134

1,14 D 435,5/437,5 ESI 135

1,62 D 404,4/406,4 ESI 136

2,16 D 412,3/414,3 ESI 137

2,31 D 400,4/402,4 ESI 138

2,41 D 400,4/402,4 ESI 139

1,62 D 432,5/434,5 ESI 140

1,75 D 428,5/430,5 ESI 141

2,54 D 445,4/447,4 ESI 142

2,50 D 428,5/430,5 ESI 143

1,95 D 401,4/403,4 ESI 144

2,34 D 496,5/498,5 ESI 145

2,31 D 429,4/431,4 ESI 146

2,11 D 401,4/403,4 ESI 147

2,48 D 469,4/471,4 ESI 148

2,36 B 394,2 ESI 149

2,35 B 394,2 ESI 150

2,35 B 394,2 ESI 151

2,15 B 378,2 ESI 152

1,64 B 433,3 ESI 153

2,56 B 418,3 ESI 154

2,16 B 420,2 ESI 155

2,34 B 404,2 ESI 156

2,43 B 406,2 ESI 157

2,12 364,2 ESI 158

1,65 B 421,2 ESI 159

2,23 B 420,3 ESI 160

2,25 B 434,3 ESI 161

1,72 B 461,4 ESI 162

1,68 B 449,4 ESI 163

1,62 B 435,3 ESI 164

1,71 B 435,3 ESI 165

2,21 B 408,3 ESI 166

1,88 B 427,3 ESI 167

1,80 B 427,3 ESI 168

1,59 B 433,3 ESI 169

2,12 B 364,2 ESI 170

2,12 B 378,2 ESI 171

2,34 B 406,3 ESI 172

2,44 B 418,3 ESI 173

2,11 B 420,3 ESI 174

2,25 B 404,3 ESI 175

0,90 B 421,5 ESI 176

1,52 B 433,3 ESI 177

2,34 B 404,3 ESI 178

2,11 B 364,2 ESI 179

2,17 B 378,3 ESI 180

2,51 B 406,3 ESI 181

1,59 B 421,2 ESI 182

2,47 B 418,2 ESI 183

2,16 B 420,2 ESI 184

2,02 B 335,2 ESI 185

1,92 B 321,2 ESI 186

1,05 C 378,4 ESI 187

0,92 C 447,5 ESI 188

1,10 C 392,5 ESI 189

1,24 C 432,5 ESI 190

1,10 C 434,5 ESI 191

1,15 C 418,4 ESI 192

0,93 C 435,4 ESI 193

1,22 C 420,5 ESI 194

2,04 C 335,4 ESI 195

0,90 C 321,3 ESI 196

2,48 B 418,3 ESI 197

2,62 B 432,3 ESI 198

2,32 B 392,3 ESI 199

2,19 B 378,2 ESI 200

2,16 B 434,3 ESI 201

1,61 B 447,4 ESI 202

1,59 B 435,3 ESI 203

2,57 B 420,3 ESI 204

1,71 B 422,2 ESI 205

1,70 B 422,3 ESI 206

1,68 B 422,3 ESI 207

2,34 B 365,1 ESI 208

1,18 C 379,4 ESI 209

1,24 C 393,4 ESI 210

1,38 C 421,5 ESI 211

1,13 C 365,4 ESI 212

1,26 C 393,4 ESI 213

1,40 C 421,5 ESI 214

1,20 C 379,4 ESI  215a  215b

385,2 ESI  216a  216b

378,1 ESI 217

1,86 B 317,2 ESI 218

1,27 C 370,2 ESI 219

0,99 B1 394,1/396,2 ESI 220

1,24 B1 364,1/366,1 ESI 221

1,02 B1 336,1/338,1 ESI

Pharmacological Data:

Description of Test:

In this test, the recovery in the intracellular pH (pH_(i)) after anacidification is ascertained, which is initiated if the NHE is capableof functioning, even under bicarbonate-free conditions. For thispurpose, the pH_(i) was determined using the pH-sensitive fluorescentdye BCECF (Calbiochem, the precursor BCECF-AM is employed).

The cells were initially loaded with BCECF. The BCECF fluorescence wasdetermined in a “Ratio Fluorescence Spectrometer” (Photon TechnologyInternational, South Brunswick, N.J., USA) at excitation wavelengths of505 and 440 nm and an emission wavelength of 535 nm and converted intothe pH_(i) using calibration curves. The cells were incubated in NH₄Clbuffer (pH 7.4) (NH₄Cl buffer: 115 mM NaCl, 20 mM NH₄Cl, 5 mM KCl, 1 mMCaCl₂, 1 mM MgSO₄, 20 mM Hepes, 5 mM glucose, 1 mg/ml BSA; a pH of 7.4is adjusted with 1 M NaOH) even during the BCECF loading. Theintracellular acidification was induced by adding 975 μl of anNH₄Cl-free buffer (see below) to 25 μl aliquots of the cells incubatedin NH₄Cl buffer. The subsequent rate of pH recovery was recorded for twominutes with NHE1, five minutes with NHE2 and three minutes with NHE3.To calculate the inhibitory potency of the tested substances, the cellswere initially investigated in buffers with which a complete orabsolutely no pH recovery took place. For complete pH recovery (100%),the cells were incubated in Na⁺-containing buffer (133.8 mM NaCl, 4.7 mMKCl, 1.25 mM CaCl₂, 1.25 mM MgCl₂, 0.97 mM Na₂HPO₄, 0.23 mM NaH₂PO₄, 5mM Hepes, 5 mM glucose, a pH of 7.0 is adjusted with 1 M NaOH). Todetermine the 0% value, the cells were incubated in an Na⁺-free buffer(133.8 mM choline chloride, 4.7 mM KCl, 1.25 mM CaCl₂, 1.25 mM MgCl₂,0.97 mM K₂HPO₄, 0.23 mM KH₂PO₄, 5 mM Hepes, 5 mM glucose, a pH of 7.0 isadjusted with 1 M NaOH). The substances to be tested were made up in theNa⁺-containing buffer. The recovery of the intracellular pH at each testconcentration of a substance was expressed as a percentage of themaximum recovery. The IC₅₀ value for the particular substance for theindividual NHE subtypes was calculated from the pH recovery percentagesusing the Sigma-Plot program. TABLE 14 Example IC₅₀ [μM], (NHE3) 1a0.075 2a 0.082 2b 0.026 6 0.670 7 0.250 10 1.000 17 0.049 21 0.814 231.507 24 0.340 29 0.318 36 0.274 48 0.349 51 0.215 60 0.202 64 0.507 810.730 87 0.418 97 0.308 113 0.279 119 0.682 144 0.695 146 0.024 1530.602 183 0.597 199 0.252 207 0.186

1. A process for preparing compounds of formula I

wherein: R1, R2, R3 and R4 are independently of one another H, F, Cl,Br, I, CN, NO₂, OH, NH₂, C_(a)H_(2a+1), C_(qq)H_(2qq−1), OC_(b)H_(2b+1),COOR10, OCOR10, COR10 or O_(x)—(CH₂)_(y)-phenyl; wherein a and b areindependently of one another 1, 2, 3, 4, 5, 6, 7 or 8, wherein thegroups C_(a)H_(2a+1) and OC_(b)H_(2b+1) independently of one another areunsubstituted or substituted where one or more H atoms are replaced by Fatoms; qq is 3, 4, 5, 6, 7 or 8, wherein the group CqqH2qq−1 isunsubstituted or substituted where one or more H atoms are replaced by Fatoms; R10 is H or C_(c)H_(2c+1); c is 1, 2, 3, 4, 5, 6, 7 or 8, whereinthe group CcH2c+1 is unsubstituted or substituted where one or more Hatoms are replaced by F atoms; x is zero or 1; y is zero, 1, 2, 3 or 4;where the phenyl ring in the group O_(x)—(CH₂)_(y)-phenyl isunsubstituted or substituted by 1-3 independently chosen from F, Cl, Br,CN, NO₂, OH, NH₂ and C_(d)H_(2d+1), d is 1, 2, 3 or 4, wherein the groupC_(d)H_(2d+1) is unsubstituted or substituted where one or more H atomsare replaced by F atoms; or R1, R2, R3 and R4 are independently of oneanother chosen from a heteroaryl with at least one heteroatom chosenfrom 1, 2, 3 or 4 N atoms, 1 oxygen atom and 1 S atom, present as ringatoms; or R1, R2, R3 and R4 are independently of one another CONR11R12or NR11R12; wherein R11 and R12 are independently of one another H,C_(e)H_(2e+1), C_(rr)H_(2rr−1); e is 1, 2, 3, 4, 5, 6, 7 or 8; rr is 3,4, 5, 6, 7, or 8, wherein the groups C_(e)H_(2e+1) and C_(rr)H_(2rr−1)independently of one another are unsubstituted or substituted where oneor more H atoms are replaced by F atoms and/or one or more CH₂ groupsare replaced by O or NR13; R13 is H or C_(f)H_(2f+1);  f is 1, 2, 3 or4, wherein the group C_(f)H_(2f+1) is unsubsitituted or substitutedwhere one or more H atoms are replaced by F atoms; or R13 and a CH₂group of R11 or R12 together with the N atom to which they are bondedform a 5- or 6-membered ring; or R11 and R12 together with the N atom towhich they are bonded form a 5-, 6- or 7-membered ring; or R11 and R12are independently of one another COR14, CSR14 or SO₂R14; wherein R14 isC_(g)H_(2g+1); g is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the groupC_(g)H_(2g+1) is unsubsitituted or substituted where one or more H atomsare replaced by F atoms, and/or one or more CH₂ groups are replaced by Oor NR13; or R1, R2, R3 and R4 are independently of one another—O_(h)—SO_(j)—R15, with h is zero or 1; i is zero, 1 or 2; R15 isC_(k)H_(2k+1), OH, OC_(l)H_(2l+1) or NR17R18; k is 1, 2, 3, 4, 5, 6, 7or 8, wherein the group C_(k)H_(2k+1) is unsubsitituted or substitutedwhere one or more H atoms are replaced by F atoms; l is 1, 2, 3, 4, 5,6, 7 or 8, wherein the group OC_(l)H_(2l+1) is unsubsitituted orsubstituted where one or more H atoms are replaced by F atoms; R17 andR18 are independently of one another H or C_(m)H_(2m+1); m is 1, 2, 3,4, 5, 6, 7 or 8, wherein the group C_(m)H_(2m+1) is unsubstituted orsubstituted where one or more H atoms is replaced by F atoms and/or oneor more CH₂ groups are replaced by O, CO, CS or NR19;  R19 is H orC_(n)H_(2n+1);  n is 1, 2, 3 or 4, wherein the group C_(n)H_(2n+1) isunsubstituted or substituted where one or more H atoms are replaced by Fatoms;  or  R19 and a CH₂ group of R17 or R18 together with the N atomto which they are bonded form a 5- or 6-membered ring; or R17 and R18together with the N atom to which they are bonded form a 5-, 6- or7-membered ring; but where R2 does not equal H in any of the foregoingdefinitions, R5 is H, C_(p)H_(2p+1), C_(ss)H_(2ss−1), COR20 or SO₂R20;wherein p is 1, 2, 3, 4, 5, 6, 7 or 8, ss is 3, 4, 5, 6, 7 or 8, R20 isC_(q)H_(2q+1); q is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the groupsC_(p)H_(2p+1), C_(ss)H_(2ss−1) and C_(q)H_(2q+1) independently of oneanother are unsubstituted or substituted where one or more H atoms arereplaced by F atoms and/or one or more CH₂ groups are replaced by O orNR21; R21 is H or C_(r)H_(2r+1); r is 1, 2, 3 or 4; wherein the groupC_(r)H_(2r+1) is unsubstituted or substituted where one or more H atomsare replaced by F atoms; R6 is H; R7, R8 and R9 are independently of oneanother —O_(v)—SO_(w)—R23; wherein v is zero or 1; w is zero, 1 or 2;R23 is C_(nn)H_(2nn+1), C_(mm)H_(2mm−1), OH, OC_(pp)H_(2pp+1) orNR25R26; nn and pp are independently of one another 1, 2, 3, 4, 5, 6, 7or 8, mm is 3, 4, 5, 6, 7 or 8, wherein the groups C_(nn)H_(2nn+1),C_(mm)H_(2mm−1) and OC_(pp)H_(2pp+1) independently of one another areunsubstituted or substituted where one or more H atoms are replaced by Fatoms; R25 and R26 are independently of one another H, CN,C_(z)H_(2z+1), or C_(zz)H_(2zz−1); z is 1, 2, 3, 4, 5, 6, 7 or 8; zz is3, 4, 5, 6, 7 or 8, wherein the group C_(z)H_(2z+1) is unsubstituted orsubstituted where one or more H atoms are replaced by F atoms and,wherein the group C_(z)H_(2z+1), is unsubstituted or substituted whereone or more H atoms are replaced by F atoms and/or one or more CH₂groups are replaced by O, CO, CS or NR27; R27 is H or C_(aa)H_(2aa+1); aa is 1, 2, 3 or 4, wherein the group C_(aa)H_(2aa+1) is unsubstitutedor substituted where one or more H atoms are replaced by F atoms; or R27and a CH₂ group of R25 or R26 together with the N atom to which they arebonded form a 5- or 6-membered ring; or R25 and R26 together with the Natom to which they are bonded form a 5-, 6- or 7-membered ring; or R7,R8 and R9 are independently of one another NR32COR30, NR32CSR30 orNR32SO_(bb)R30; R30 is H, C_(cc)H_(2cc+1), C_(yy)H_(2yy−1), pyrrolidinylor piperidinyl, wherein the pyrrolidinyl or piperidinyl is unsubstitutedor substituted where a CH₂ group is replaced by O or NR33; R32 and R33are independently of one another H or C_(h)H_(2h+1); bb is 2 or 3; cc is1, 2, 3, 4, 5, 6, 7 or 8; yy is 3, 4, 5, 6, 7 or 8; h is 1, 2, 3, 4, 5,6, 7 or 8, wherein the group C_(h)H_(2h+1) is unsubstituted orsubstituted where one or more H atoms are replaced by F atoms, andwherein the groups C_(cc)H_(2cc+1) and C_(yy)H_(2yy−1) independently ofone another are unsubstituted or substituted where one or more H atomsare replaced by F atoms and/or one or more CH₂ groups are replaced byNR31 and/or one CH₂ group are replaced by O; R31 is H, C_(kk)H_(2kk+1),COR65 or SO₂ R65;  kk is 1, 2, 3, or 4; wherein the groupC_(kk)H_(2kk+1) is unsubstituted or substituted where one or more Hatoms are replaced by F atoms,  R65 is H, or C_(xx)H_(2xx+1);  xx is 1,2, 3 or 4, wherein the group C_(xx)H_(2xx+1) is unsubstituted orsubstituted where one or more H atoms are replaced by F atoms; or R31together with a CH₂ group of R30 forms a 5-, 6- or 7-membered ring; orR30 is a 5- or 6-membered heteroaryl with at least one hetero atomchosen from 1, 2, 3 or 4 N atoms, zero, 1 S atom and 1 O atom, which isunsubstituted or substituted by up to three substituents chosen from F,Cl, Br, I, C_(oo)H_(2oo+1), and NR7OR71; R70 and R71 are independentlyof one another H, C_(uu)H_(2uu+1) or COR72; R72 is H, orC_(vv)H_(2vv+1); oo, uu and w are independently of one another 1, 2, 3,4, 5, 6, 7 or 8, wherein the groups C_(oo)H_(2oo+1), C_(uu)H_(2uu+1) andC_(vv)H_(2vv+1) independently of one another are unsubstituted orsubstituted where one or more H atoms are replaced by F atoms; or R7, R8and R9 are independently of one another H, F, Cl, Br, I, NO₂, CN, OH,NH₂, C_(ee)H_(2ee+1), C_(ww)H_(2ww−1), OC_(ff)H_(2ff+1), NR4OR41,CONR40R41, COOR42, COR42 or OCOR42, ee and ff are independently of oneanother 1, 2, 3, 4, 5, 6, 7 or 8; ww is 3, 4, 5, 6, 7 or 8, wherein thegroups C_(ee)H_(2ee+1), C_(ww)H_(2ww−1) and OC_(ff)H_(2ff+1)independently of one another are unsubstituted or substituted where oneor more H atoms are replaced by F atoms; R40 and R41 are independentlyof one another H, C_(tt)H_(2tt+1) or C(NH)NH₂; tt is 1, 2, 3, 4, 5, 6, 7or 8, wherein the group C_(tt)H_(2tt+1) is unsubstituted or substitutedwhere one or more H atoms are replaced by F atoms and/or where one ormore CH₂ groups are replaced by O or NR44; R44 is H or C_(gg)H_(2gg+1);gg is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group C_(gg)H_(2gg+1) isunnsubstituted or substituted where one or more H atoms are replaced byF atoms or R44 forms a 5- or 6-membered ring together with a (CH₂) groupof R40 or R41 and the N atom to which they are bound; or R40 and R41with the N atom to which they are bonded form a 5- or 6-membered ring;R42 is H or C_(hh)H_(2hh+1); hh is 1, 2, 3, 4, 5, 6, 7 or 8, wherein thegroup C_(hh)H_(2hh+1) is unnsubstituted or substituted where one or moreH atoms are replaced by F atoms; with the proviso that two substituentschosen from the group R7, R8 and R9 can not simultaneously be OH andOCH₃, and that at least one of the substituents R7, R8 and R9 is chosenfrom CONR40R41, —O_(v)—SO_(w)—R²³, NR32COR30, NR32CSR30 andNR32SO_(bb)R30; or a pharmaceutically acceptable salt thereof, or atrifluoroacetate thereof in any stereoisomeric form, or a mixture of anysuch compounds in any ratio; which process comprises converting thealcohol of formula VII in the presence of an acid, to the compound offormula I

where, in the compounds of the formulae VII R1 to R5 and R7 to R9 areeach as defined in formula I.
 2. A process for preparing compounds offormula I

wherein: R1, R2, R3 and R4 are independently of one another H, F, Cl,Br, I, CN, NO₂, OH, NH₂, C_(a)H_(2a+1), C_(qq)H_(2qq−1), OC_(b)H_(2b+1),COOR10, OCOR10, COR10 or O_(x)—(CH₂)_(y)-Phenyl; wherein a and b areindependently of one another 1, 2, 3, 4, 5, 6, 7 or 8, wherein thegroups C_(a)H_(2a+1) and OC_(b)H_(2b+1) independently of one another areunsubstituted or substituted where one or more H atoms are replaced by Fatoms; qq is 3, 4, 5, 6, 7 or 8, wherein the group CqqH2qq−1 isunsubstituted or substituted where one or more H atoms are replaced by Fatoms; R10 is H or C_(c)H_(2c+1); c is 1, 2, 3, 4, 5, 6, 7 or 8, whereinthe group CcH2c+1 is unsubstituted or substituted where one or more Hatoms are replaced by F atoms; x is zero or 1; y is zero, 1, 2, 3 or 4;where the phenyl ring in the group O_(x)—(CH₂)_(y)-phenyl isunsubstituted or substituted by 1-3 independently chosen from F, Cl, Br,CN, NO₂, OH, NH₂ and C_(d)H_(2d+1), d is 1, 2, 3 or 4, wherein the groupC_(d)H_(2d+1) is unsubstituted or substituted where one or more H atomsare replaced by F atoms; or R1, R2, R3 and R4 are independently of oneanother chosen from a heteroaryl with at least one heteroatom chosenfrom 1, 2, 3 or 4 N atoms, 1 oxygen atom and 1 S atom, present as ringatoms; or R1, R2, R3 and R4 are independently of one another CONR11R12or NR11R12; wherein R11 and R12 are independently of one another H,C_(e)H_(2e+1), C_(rr)H_(2rr−1); e is 1, 2, 3, 4, 5, 6, 7 or 8; rr is 3,4, 5, 6, 7, or 8, wherein the groups C_(e)H_(2e+1) and C_(rr)H_(2rr−1)independently of one another are unsubstituted or substituted where oneor more H atoms are replaced by F atoms and/or one or more CH₂ groupsare replaced by O or NR13; R13 is H or C_(f)H_(2f+1);  f is 1, 2, 3 or4, wherein the group C_(f)H_(2f+1) is unsubsitituted or substitutedwhere one or more H atoms are replaced by F atoms; or R13 and a CH₂group of R11 or R12 together with the N atom to which they are bondedform a 5- or 6-membered ring; or R11 and R12 together with the N atom towhich they are bonded form a 5-, 6- or 7-membered ring; or R11 and R12are independently of one another COR14, CSR14 or SO₂R14; wherein R14 isC_(g)H_(2g+1); g is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the groupC_(g)H_(2g+1) is unsubsitituted or substituted where one or more H atomsare replaced by F atoms, and/or one or more CH₂ groups are replaced by Oor NR13; or R1, R2, R3 and R4 are independently of one another—O_(h)—SO_(j)—R15, with h is zero or 1; j is zero, 1 or 2; R15 isC_(k)H_(2k+1), OH, OC_(l)H_(2l+1) or NR17R18; k is 1, 2, 3, 4, 5, 6, 7or 8, wherein the group C_(k)H_(2k+1) is unsubsitituted or substitutedwhere one or more H atoms are replaced by F atoms; l is 1, 2, 3, 4, 5,6, 7 or 8, wherein the group OC_(l)H_(2l+1) is unsubsitituted orsubstituted where one or more H atoms are replaced by F atoms; R17 andR18 are independently of one another H or C_(m)H_(2m+1); m is 1, 2, 3,4, 5, 6, 7 or 8, wherein the group C_(m)H_(2m+1) is unsubstituted orsubstituted where one or more H atoms is replaced by F atoms and/or oneor more CH₂ groups are replaced by O, CO, CS or NR19;  R19 is H orC_(n)H_(2n+1);  n is 1, 2, 3 or 4, wherein the group C_(n)H_(2n+1) isunsubstituted or substituted where one or more H atoms are replaced by Fatoms;  or  R19 and a CH₂ group of R17 or R18 together with the N atomto which they are bonded form a 5- or 6-membered ring; or R17 and R18together with the N atom to which they are bonded form a 5-, 6- or7-membered ring; but where R2 does not equal H in any of the foregoingdefinitions, R5 is H, C_(p)H_(2p+1), C_(ss)H_(2ss−1), COR20 or SO₂R20;wherein p is 1, 2, 3, 4, 5, 6, 7 or 8, ss is 3, 4, 5, 6, 7 or 8, R20 isC_(q)H_(2q+1); q is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the groupsC_(p)H_(2p+1), C_(ss)H_(2ss−1) and C_(q)H_(2q+1) independently of oneanother are unsubstituted or substituted where one or more H atoms arereplaced by F atoms and/or one or more CH₂ groups are replaced by O orNR21; R21 is H or C_(r)H_(2r+1); r is 1, 2, 3 or 4; wherein the groupC_(r)H_(2r+1) is unsubstituted or substituted where one or more H atomsare replaced by F atoms; R6 is C_(s)H_(2s+1), s is 1, 2, 3, 4, 5, 6, 7or 8; R7, R8 and R9 are independently of one another —O_(v)—SO_(w)—R23;wherein v is zero or 1; w is zero, 1 or 2; R23 is C_(nn)H_(2nn+1),C_(mm)H_(2mm−1), OH, OC_(pp)H_(2pp+1) or NR25R26; nn and pp areindependently of one another 1, 2, 3, 4, 5, 6, 7 or 8, mm is 3, 4, 5, 6,7 or 8, wherein the groups C_(nn)H_(2nn+1), C_(mm)H_(2mm−1) andOC_(pp)H_(2pp+1) independently of one another are unsubstituted orsubstituted where one or more H atoms are replaced by F atoms; R25 andR26 are independently of one another H, CN, C_(z)H_(2z+1), orC_(zz)H_(2zz−1); z is 1, 2, 3, 4, 5, 6, 7 or 8; zz is 3, 4, 5, 6, 7 or8, wherein the group C_(z)H_(2z+1) is unsubstituted or substituted whereone or more H atoms are replaced by F atoms and, wherein the groupC_(z)H_(2z+1), is unsubstituted or substituted where one or more H atomsare replaced by F atoms and/or one or more CH₂ groups are replaced by O,CO, CS or NR27; R27 is H or C_(aa)H_(2aa+1);  aa is 1, 2, 3 or 4,wherein the group C_(aa)H_(2aa+1) is unsubstituted or substituted whereone or more H atoms are replaced by F atoms; or R27 and a CH₂ group ofR25 or R26 together with the N atom to which they are bonded form a 5-or 6-membered ring; or R25 and R26 together with the N atom to whichthey are bonded form a 5-, 6- or 7-membered ring; or R7, R8 and R9 areindependently of one another NR32COR30, NR32CSR30 or NR32SO_(bb)R30; R30is H, C_(cc)H_(2cc+1), C_(yy)H_(2yy−1), pyrrolidinyl or piperidinyl,wherein the pyrrolidinyl or piperidinyl is unsubstituted or substitutedwhere a CH₂ group is replaced by O or NR33; R32 and R33 areindependently of one another H or C_(h)H_(2h+1); bb is 2 or 3; cc is 1,2, 3, 4, 5, 6, 7 or 8; yy is3,4,5,6,7or8; h is 1, 2, 3, 4, 5, 6, 7 or 8,wherein the group C_(h)H_(2h+1) is unsubstituted or substituted whereone or more H atoms are replaced by F atoms, and wherein the groupsC_(cc)H_(2cc+1) and C_(yy)H_(2yy−1) independently of one another areunsubstituted or substituted where one or more H atoms are replaced by Fatoms and/or one or more CH₂ groups are replaced by NR31 and/or one CH₂group are replaced by O; R31 is H, C_(kk)H_(2kk+1), COR65 or SO₂ R65; kk is 1, 2, 3, or 4; wherein the group C_(kk)H_(2kk+1) is unsubstitutedor substituted where one or more H atoms are replaced by F atoms,  R65is H, or C_(xx)H_(2xx+1);  xx is 1, 2, 3 or 4, wherein the groupC_(xx)H_(2xx+1) is unsubstituted or substituted where one or more Hatoms are replaced by F atoms; or R31 together with a CH₂ group of R30forms a 5-, 6- or 7-membered ring; or R30 is a 5- or 6-memberedheteroaryl with at least one hetero atom chosen from 1, 2, 3 or 4 Natoms, zero, 1 S atom and 1 O atom, which is unsubstituted orsubstituted by up to three substituents chosen from F, Cl, Br, I,C_(oo)H_(2oo+1), and NR70R71; R70 and R71 are independently of oneanother H, C_(uu)H_(2uu+1) or COR72; R72 is H, or C_(vv)H_(2vv+1); oo,uu and w are independently of one another 1, 2, 3, 4, 5, 6, 7 or 8,wherein the groups C_(oo)H_(2oo+1), C_(uu)H_(2uu+1) and C_(vv)H_(2vv+1)independently of one another are unsubstituted or substituted where oneor more H atoms are replaced by F atoms; or R7, R8 and R9 areindependently of one another H, F, Cl, Br, I, NO₂, CN, OH, NH₂,C_(ee)H_(2ee+1), C_(ww)H_(2ww−1), OC_(ff)H_(2ff+1), NR4OR41, CONR4OR41,COOR42, COR42 or OCOR42, ee and ff are independently of one another 1,2, 3, 4, 5, 6, 7 or 8; ww is 3, 4, 5, 6, 7 or 8, wherein the groupsC_(ee)H_(2ee+1), C_(ww)H_(2ww−1) and OC_(ff)H_(2ff+1) independently ofone another are unsubstituted or substituted where one or more H atomsare replaced by F atoms; R40 and R41 are independently of one another H,C_(tt)H_(2tt+1) or C(NH)NH₂; it is 1, 2, 3, 4, 5, 6, 7 or 8, wherein thegroup C_(tt)H_(2tt+1) is unsubstituted or substituted where one or moreH atoms are replaced by F atoms and/or where one or more CH₂ groups arereplaced by O or NR44; R44 is H or C_(gg)H_(2gg+1); gg is 1, 2, 3, 4, 5,6, 7 or 8, wherein the group C_(gg)H_(2gg+1) is unnsubstituted orsubstituted where one or more H atoms are replaced by F atoms or R44forms a 5- or 6-membered ring together with a (CH₂) group of R40 or R41and the N atom to which they are bound; or R40 and R41 with the N atomto which they are bonded form a 5- or 6-membered ring; R42 is H orC_(hh)H_(2hh+1); hh is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the groupC_(hh)H_(2hh+1) is unnsubstituted or substituted where one or more Hatoms are replaced by F atoms; with the proviso that two substituentschosen from the group R7, R8 and R9 can not simultaneously be OH andOCH₃, and that at least one of the substituents R7, R8 and R9 is chosenfrom CONR40R41, —O_(v)—SO_(w)—R23, NR32COR30, NR32CSR30 andNR32SO_(bb)R30; or a pharmaceutically acceptable salt thereof, or atrifluoroacetate thereof in any stereoisomeric form, or a mixture of anysuch compounds in any ratio; which process comprises converting theamide of formula XII to the compound of formula I

where, in the compounds of the formulae XII R1 to R9 are each as definedin formula I.